The no-carrier-added synthesis of bromine-76 labeled alkenyl and alkynyl bromides using organotrifluoroborates

Article abstract of DOI:10.1002/jlcr.1025

A straightforward radiobromination procedure has been developed for the construction of radiobrominated alkenyl and alkynyl bromides. The organotrifluoroborates used as the reactive intermediates are unique in that they are quite polar and thus readily separated from the desired products. Copyright

Full text of DOI:10.1002/jlcr.1025

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 11–15.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1025
Research Article
The no-carrier-added synthesis of bromine-76
labeled alkenyl and alkynyl bromides using
organotrifluoroborates
George W. Kabalka*, Arjun R. Mereddy and James F. Green
Department of Chemistry and Radiology, University of Tennessee, Knoxville,
TN 37996, USA
Summary
A straightforward radiobromination procedure has been developed for the construc-
tion of radiobrominated alkenyl and alkynyl bromides. The organotrifluoroborates
used as the reactive intermediates are unique in that they are quite polar and
thus readily separated from the desired products. Copyright # 2005 John Wiley &
Sons, Ltd.
Key Words: no-carrier-added; alkenyl bromide; alkynyl bromide; radiobromination;
organotrifluoroborates
Introduction
The halogens have great potential in radiopharmaceutical design because of
their ready availability and chemical reactivity. Traditionally, most radio-
halogenation studies have been directed toward the insertion of radioiodine
but, in recent years, there has been increased interest in radiobromination
techniques due to the availability of cyclotron produced bromine isotopes and
1
–4
the greater stability of organic bromides when compared to organic iodides.
We recently reported a new radioiodination procedure involving the
reaction of organotrifluoroborates with sodium iodide in the presence of mild
5,6
oxidizing agents.
Organotrifluoroborates have proven to be versatile
intermediates in organic synthesis because of their selective chemical activity.
Interestingly, they are crystalline ionic solids that are stable to both air and
*Correspondence to: George W. Kabalka, University of Tennessee, Rm. 612 Buehler Hall, Knoxville,
TN 37996, USA. E-mail: kabalka@utk.edu
Contract/grant sponsor: The US Department of Energy; contract/grant number: DE-FG02-04ER63895
Contract/grant sponsor: Robert H. Cole Foundation
Contract/grant sponsor: NCI; contract/grant number: R24CA86307
Copyright # 2005 John Wiley & Sons, Ltd.
Received 8 September 2005
Revised 17 October 2005
Accepted 19 October 2005

1
2
G. W. KABALKA ET AL.
water for extended periods, and they are readily prepared from the
7
–10
corresponding boronic acids by addition of KHF2.
Yet, trifluoroborates
salts have proven to be as chemically reactive as boronic acids in organic
syntheses and are far simpler to remove from reaction mixtures due to their
ionic nature. We wish to report a rapid and high yield synthesis of high specific
activity, bromine-76 labeled alkenyl and alkynyl bromides from the
corresponding organotrifluoroborates, Scheme 1. The fact that only the
products are lipophilic makes the new reaction potentially useful for a variety
of Nuclear Medicine imaging applications.
Results and discussion
A number of bromine-76 labeled alkenyl and alkynyl bromides were prepared
from the corresponding alkenyl- and alkynyltrifluoroborate salts. The results
are summarized in Tables 1 and 2. Organotrifluoroborates 2a2f and 5a2j
6
were prepared according to the literature procedure and then subjected to the
7
6
radiobromination procedure using no-carrier added NH4 Br and peracetic
acid in 50% aqueous THF to yield 3a2f and 6a2j. Bromination of alkenyl
trifluoroborates 2a2f was found to proceed with retention of configuration,
providing ready access to a variety of (E) and (Z) alkenyl bromides. The
radiochemical purity of the products typically exceed 98% and the overall
radiochemical yields are good. The radiobromination of alkynyltrifluorobo-
Scheme 1. Radiobromination of alkenyl and alkynyl trifluoroborates
Table 1. Synthesis of no-carrier added bromine-76 labeled alkenyl bromines
Starting material
R
Product
Radiochemical
yields (%)
2
2
2
2
2
2
a
b
c
d
e
f
Phenyl (trans)
Phenyl (cis)
4-Methylphenyl
4-Chlorophenyl
4-Trifluoromethylphenyl
Heptyl
3a
3b
3c
3d
3e
3f
70
69
74
65
56
48
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J Label Compd Radiopharm 2006; 49: 11–15

RAPID INCORPORATION OF BROMINE-76
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Table 2. Synthesis of no-carrier added bromine-76 labeled alkynyl bromines
Starting material
R
Product
Radiochemical
yields (%)
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
Phenyl
6a
6b
6c
6d
6e
6f
6g
6h
6i
80
82
84
78
64
81
68
76
78
65
4-Methoxyphenyl
4-Methylphenyl
4-Cyanophenyl
l-Cyclohexenyl
Hexyl
t-Butyl
l-Chloropropyl
4-tert-Butyldimethylsilyloxybutyl
4-Hydroxybutyl
j
6j
rates 5a2j also produced radiochemical purities in excess of 98% and overall
radiochemical yields >65%. It is noteworthy that these purities are, achieved
(as confirmed by radio-HPLC and radio TLC) by simply passing the reaction
mixture through two Sep-pak cartridges (one silica gel and one alumina
cartridge). The simple isolation procedure is a consequence of the fact that the
trifluoroborate starting materials are ionic and the products are lipophilic.
This straightforward work up was also noted in the earlier radioiodination
6
studies.
Experimental
Radio thin layer chromatography was carried out on a Bioscan Ar-2000
imaging scanner. All boronic acids were purchased from Aldrich Chemical
Company and Frontier Scientific, Inc. and used to prepare the potassium
10
trifluoroborates. The stable bromine analogues used for R measurements
f
1
1
76
were prepared according to the literature procedure. NH4 Br was obtained
from Washington University School of Medicine, St. Louis, MO, USA. The
specific activity of the bromine-76 utilized was 1.09 Ci/mmole. All the reactions
were carried out using dry solvents under an inert atmosphere.
Analyses of the products was performed by reversed-phase HPLC (Waters
Model 510 pump and Waters 680 gradient controller) equipped with a UV
detector (Waters Model 440) operating at 254 nm and a photoiodide radio
detector (ORTEC Model 994). A Waters m Bondapak C-18 (3.9 ꢀ 300 mm)
was utilized with a mobile phase gradient of 35% aqueous acetonitrile at a
flow rate of 1.0 ml/min. Identification of all radioactive products was
confirmed by co-elution with the corresponding non radioactive bromide
1
1
compound. In all cases the radiochemical purity of the product was >98%.
Specific activity was determined by quantitation (using experimentally
determined dilution–response curves) of the UV response of a known amount
of radioactivity injected onto the Waters HPLC system.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 11–15

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G. W. KABALKA ET AL.
76
Radiosynthesis of 1-[ Br]bromo-2-phenylethyne (representative procedure)
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6
No-carrier-added NH4 Br (140 mCi in 0.1% aqueous NH OH) was placed in
4
ꢁ2
a 2 ml Wheaton vial containing trifluoroborate 5a (100 ml of 5.2 ꢀ 10
solution in 50% aqueous tetrahydrofuran). To this was added peracetic acid
100 ml, 0.3% solution in methanol). The reaction vial was sealed, covered with
M
(
aluminum foil, and the mixture stirred for 10 min at room temperature. The
radiobrominated product was isolated by passing the reaction mixture through
two dry Sep-pak cartridges (one silica and one alumina) to remove ionic
material, using hexanes (6 ml) as eluent. The homogeneous organic eluent was
analyzed using C-18 reversed phase chromatography with aqueous acetonitrile
(acetonitrile: water=65:35) as the mobile phase (flow rate ¼ 1:0 ml=min). The
retention time of 6a was 10 min. The radiochemical yield was 80% and
76
radiochemical purity of the l-[ Br]bromo-2-phenylethyne, 6a, was >98%
radio-HPLC and radio TLC). Recovery of the essentially pure product was
(
achieved by removing the solvent under a stream of dry nitrogen (additional
purification can be achieved by injecting this product onto the HPLC utilizing
the same conditions used for radiochemical analysis). The total synthesis time
was 20 min. The specific activity was determined to be 250 Ci/mmol. The
alkenyltrifluoroborates were radiobrominated using a parallel procedure.
Conclusion
A convenient, high yield radiobromination procedure for preparing no-
carrier-added radiobrominated alkenyl and alkynyl bromides has been
developed. Because of the stability of the precursor trifluoroborates, the
procedure is well suited for nuclear medicine imaging applications.
Acknowledgements
We wish to thank the US Department of Energy (DE-FG02-04ER63895) and
the Robert H. Cole Foundation for Support of this research. The production
of bromine-76 at the University of Washington School of Medicine is
supported by the NCI grant R24CA86307.
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