Radical-mediated carboxylation of alkyl iodides with [11C]carbon monoxide in solvent mixtures

Article abstract of DOI:10.1021/jo047806s

(Chemical Equation Presented) [carboxyl-¹¹C]Carboxylic acids were prepared from alkyl iodides via photoinitiated radical reactions using 10^-8 mol of [¹¹C]carbon monoxide in binary and ternary homogeneous solvent mixtures. Short-(isobutyric), medium-, and long-chain saturated fatty acids (heptadecanoic) were labeled with isolated decay-corrected radiochemical yields ranging from 55% to 70% in 5-7-min reactions. The conversion of [¹¹C]carbon monoxide to products reached 80-90%. To obtain good yields in the reactions performed in water-acetonitrile and water-THF mixtures, the addition of tetrabutylammonium hydroxide or potassium hydroxide was essential. The carboxylation was efficient for primary and secondary alkyl iodides. The carboxylation of tertiary iodides was feasible for 1-iodoadamantane but not for tert-butyl iodide. The dependence of the radiochemical yields on reaction time, photoirradiation conditions, and organic and inorganic additives was studied. The method provides a one-step route to [carboxyl-¹¹C]carboxylic acids; traditional methods, in contrast, would require several steps. For example, using the devised reaction conditions, 3.19 GBq of purified [1-¹¹C]1,10-decanedicarboxylic acid (specific radioactivity 188 GBq/μmol) was obtained within 35 min of the end of 10 μAh bombardment. (1-¹³C)4-Phenylbutyric acid was synthesized using (¹³C)-carbon monoxide for identifying the labeling position with ¹H and ¹³C NMR.

Full text of DOI:10.1021/jo047806s

Radical-Mediated Carboxylation of Alkyl Iodides with [11C]Carbon
Monoxide in Solvent Mixtures
Oleksiy Itsenko† and Bengt Långstro¨m*,†,‡
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 531,
S-751 21 Uppsala, Sweden, and Uppsala Imanet AB, Box 967, S-751 09 Uppsala, Sweden
bengt.langstrom@uppsala.imanet.se
Received December 15, 2004
[carboxyl-11C]Carboxylic acids were prepared from alkyl iodides via photoinitiated radical reactions
using 10-8 mol of [11C]carbon monoxide in binary and ternary homogeneous solvent mixtures. Short-
(isobutyric), medium-, and long-chain saturated fatty acids (heptadecanoic) were labeled with
isolated decay-corrected radiochemical yields ranging from 55% to 70% in 5-7-min reactions. The
conversion of [11C]carbon monoxide to products reached 80-90%. To obtain good yields in the
reactions performed in water-acetonitrile and water-THF mixtures, the addition of tetrabut-
ylammonium hydroxide or potassium hydroxide was essential. The carboxylation was efficient for
primary and secondary alkyl iodides. The carboxylation of tertiary iodides was feasible for
1-iodoadamantane but not for tert-butyl iodide. The dependence of the radiochemical yields on
reaction time, photoirradiation conditions, and organic and inorganic additives was studied. The
method provides a one-step route to [carboxyl-11C]carboxylic acids; traditional methods, in contrast,
would require several steps. For example, using the devised reaction conditions, 3.19 GBq of purified
[1-11C]1,10-decanedicarboxylic acid (specific radioactivity 188 GBq/µmol) was obtained within 35
min of the end of 10 µAh bombardment. (1-13C)4-Phenylbutyric acid was synthesized using (13C)-
1
carbon monoxide for identifying the labeling position with H and 13C NMR.
Introduction
carbon monoxide and aryl or benzyl halides (or triflates)
in palladium-mediated reactions.6 The last method, un-
like the first two, is a versatile one-step procedure;
however, it has limited value for the labeling of aliphatic
acids due to competing â-elimination from alkyl halides.
This paper presents a convenient one-pot method,
based on free-radical carbonylation with [11C]carbon
monoxide, for the labeling of aliphatic carboxylic acids.
Though in general the methodology for synthesizing
carboxylic acid derivatives by free-radical carbonylation
Biologically active compounds labeled with 11C are
extensively used as tracers in positron emission tomog-
raphy (PET), a noninvasive molecular imaging technique
that has been recognized as an important tool in medical
and pharmaceutical applications.1 Carboxylic functional-
ity is found in many bioactive compounds, so it is a
potential position for labeling with a short-lived, positron-
emitting radionuclide 11C (half-life 20.3 min).
At present, [carboxyl-11C]carboxylic acids are commonly
prepared using [11C]carbon dioxide or hydrogen [11C]-
cyanide,2,3 by carbonation of Grignard reagents4 or hy-
drolysis of intermediate nitriles,5 respectively. Aromatic
[carboxyl-11C] acids may also be synthesized from [11C]-
(3) Kihlberg, T.; Antoni, G.; Långstro¨m, B. In Handbook of Nuclear
Chemistry; Ve´rtez, A., Nagy, S., Klencsa´r, Z., Eds.; Kluwer Academic
Publishers: Amsterdam, The Netherlands, 2003; Vol. 4, pp 119-165.
(4) Kawashima, H.; Yajima, K.; Kuge, Y.; Hashimoto, N.; Miyake,
Y. J. Label. Compd. Radiopharm. 1997, 39, 181-193. Yajima, K.;
Kawashima, H.; Hashimoto, N.; Miyake, Y. J. Phys. Chem. 1996,
14936-14940.
* Address correspondence to this author.
† Uppsala University.
(5) Antoni, G.; Långstro¨m, B. J. Label. Compd. Radiopharm. 1989,
27, 571-576. Takahashi, T.; Ido, T.; Hatano, K.; Iwata, R.; Nakanishi,
H. Appl. Radiat. Isot. 1990, 649-654. More references to the prepara-
tion of [11C]acids may be found in: Iwata, R. Reference Book for PET
‡ Uppsala Imanet AB.
(1) Principles of Nuclear Medicine, 2nd ed.; Wagner, H. N. J., Szabo,
Z., Buchanan, J. W., Eds.; W. B. Saunders Co.: Philadelphia, PA, 1995.
(2) Antoni, G.; Kihlberg, T.; Långstro¨m, B. In Handbook of Radio-
pharmaceuticals: Radiochemistry and Applications; Welch, M. J.,
Redvanly, C. S., Eds.; John Wiley & Sons Ltd.: Chichester, UK, 2003;
pp 141-194.
Radiopharmaceuticals;
http://kakuyaku.cyric.tohoku.ac.jp/public/
Reference%20Book%202004c%20for%20web.pdf (accessed Nov 2004).
(6) Karimi, F.; Långstro¨m, B. J. Chem. Soc., Perkin Trans. 1 2002,
2256-2259.
10.1021/jo047806s CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/19/2005
2244
J. Org. Chem. 2005, 70, 2244-2249

Radical Carboxylation of Alkyl Iodides with 11CO
SCHEME 1a
TABLE 1. Effect of the Organic Component in Mixed
Solvents on Radiochemical Yield of
[1-11C]4-Phenylbutyric Acida,d
a Typically, the initial concentration of iodide in a solvent
mixture was 0.2 mM. The partial pressure of [11C]carbon monoxide
in the reactor during the reaction was in the region of 200-800 Pa
due to dilution with a carrier gas. The total pressure in the reactor
was 40 MPa. The amount of reacted [11C]carbon monoxide is
referred to in the text as “the conversion of [11C]carbon monoxide”.
The percent ratio of the expected labeled product to the total
amount of radioactivity in the crude product was determined by
analytical HPLC, and is referred to as “the radiochemical purity
of the crude product” or, in the tables, simply as “purity”. All yields
set forth in this paper are decay-corrected radiochemical yields.
The “yields determined by HPLC” were calculated as the product
of “the conversion of [11C]carbon monoxide” and “the purity of the
crude product” divided by 100.
convn of
purity
(%)b
yield
(%)c
no. of
runs
organic solvent
[
11C]O (%)
NMP
acetonitrile
THF
21 ( 4
45 ( 1
57 ( 2
92 ( 1
76 ( 2
81 ( 4
19 ( 3
34 ( 1
49 ( 3
2
2
3
a Other reaction conditions: 30 °C, photoirradiation 300-400
nm, reaction time 6 min 40 s. b Decay-corrected radiochemical yield
determined by LC. c Decay-corrected radiochemical yield deter-
mined by LC. d The asterisk marks the label position.
lation of iodooctane has been reported,12 but the yield of
nonanoic acid was low.
of alkyl iodides has been comprehensively developed,7,8
the synthesis of carboxylic acids has evoked little interest.
The mechanism of radical-mediated carbonylation7
consists of several steps of both radical and ionic type.
In this reaction the acyl iodide, reversibly formed via free
radical chain reaction, is trapped by a nucleophile to yield
a carboxylic acid derivative. The solvent effects,7,15,16 as
our previous study showed,17 may be expediently used
to tune the reactivity in order to improve the synthesis.
According to our observations, the hydroxy group could
not efficiently compete with the amino group in radical-
mediated labeling reactions. Water therefore was thought
to be significantly less reactive than amines toward the
acyl iodide, and in order to synthesize acids at good yields
it was necessary to compensate for the low reactivity by
using high concentrations of water or to increase the
strength of the nucleophile, e.g., to use hydroxide anion.
Several water-miscible organic solvents were investi-
gated. N-Methyl-2-pyrrolidone, which provided an ap-
propriate medium for analogous reactions with amines
leading to labeled amides,17 did not serve equally well in
synthesizing [11C ]acids (Table 1). The reactions carried
out in acetonitrile-water and THF-water mixtures gave
higher yields. Various surfactants were also investigated;
however, the chemical selectivity was low, as has been
reported.12 Surfactants also occasionally affected LC
separation unfavorably and hampered the purification
process, which was undesirable considering the time
restrictions.
The preparative procedures for labeling with 11C must
meet several requirements, and these were taken into
account in the current study. The synthetic procedures
and workup are subject to time constraints9 associated
with the short lifetime of the radionuclide. Synthesis with
[11C]carbon monoxide is necessarily microscale,10 owing
to the method of production of the radioactive carbon,
with a consequent influence on reaction kinetics.11 Other
important issues, especially in PET tracer applications,
are specific radioactivity and ease of purification of the
labeled product.
Results and Discussion
Preparing carboxylic acids from alkyl iodides (Scheme
1) is challenged by the requirement to bring together
lipophilic reactants and water in the reaction medium.
Formation of carboxylic acids was observed12 when
radical carbonylation was performed in water using
surfactants. The reactions were, however, unselective,
and the product (acid, ester, or a mixture of both)
apparently depended on the hydrophobicity of the iodide
substrate. We used semiautomatic synthetic equipment13
to carry out reactions with [11C]carbon monoxide, and
handling heterogeneous reactant solutions proved to be
technically difficult. For this reason, and intending to
obtain proper chemical selectivity, we turned to the use
of solvent mixtures14 to overcome the immiscibility issue.
The use of the ethanol-water mixture for the carbony-
Water,18 a nucleophilic reactant in this reaction, is also
a cosolvent when taken at high concentrations. Acyl
radicals, having a more polar character than parent alkyl
radicals and carbon monoxide,16 should be stabilized in
polar media. The reversibility of the addition of alkyl
radicals to carbon monoxide7 implies that with increased
solvent polarity the rate of decarbonylation would de-
crease. Use of a polar reaction medium also increases the
rate of the ionic step: the acylation of a nucleophile.
Compared to nonpolar solvents, polar solvents, besides
their beneficial role, also promote some unwanted side
reactions, such as solvolysis of the alkyl iodides, elimina-
(7) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev.
1999, 1991-2069.
(8) Ryu, I. Chem. Soc. Rev. 2001, 16-25. Ryu, I.; Miyazato, H.;
Kuriyama, H.; Matsu, K.; Tojino, M.; Fukuyama, T.; Minakata, S.;
Komatsu, M. J. Am. Chem. Soc. 2003, 125, 5632-5633.
(9) Långstro¨m, B.; Kihlberg, T.; Bergstro¨m, M.; Antoni, G.; Bjork-
man, M.; Forngren, B. H.; Forngren, T.; Hartvig, P.; Markides, K.;
Yngve, U.; Ogren, M. Acta Chem. Scand. 1999, 651-669.
(10) Fowler, J. S.; Wolf, A. P. Acc. Chem. Res. 1997, 181-188.
(11) Långstro¨m, B.; Bergson, G. Radiochem. Radioanal. Lett. 1980,
47-54.
(12) Sugiura, M.; Hiroyuki, H.; Kobayashi, S. Chem. Lett. 2003, 32,
898-899.
(15) Kurnyshova, O. A.; Gristan, N. P.; Tsentalovich, Yu. P. Phys.
Chem. Chem. Phys. 2001, 3677-3682.
(13) Kihlberg, T.; Långstro¨m, B. Method and apparatus for produc-
tion and use of [11C]carbon monoxide in labeling synthesis; PCT
international application PCT/SE02/01222.
(16) Zhang, X.; Nau, W. M. J. Phys. Org. Chem. 2000, 634-639.
(17) Itsenko, O.; Kihlberg, T.; Långstro¨m, B. J. Org. Chem. 2004,
4356-4360.
(14) Fialkov, Y. Y.; Chumak V. L. In Handbook of Solvents; Wypych,
G., Ed.; Chem. Tec. Publishing: Toronto, Canada, 2001; pp 505-564.
(18) Synthetic radical reactions in aqueous solutions are reviewed
in: Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674-686.
J. Org. Chem, Vol. 70, No. 6, 2005 2245

Itsenko and Långstro¨m
TABLE 2. Decay-Corrected Radiochemical Yields of
[1-11C]Acids Obtained under Various Photoirradiation
Conditionsa
TABLE 3. Effect of Reaction Conditions and Added
Base on Yield of [1-11C]Tridecanoic Acid
convn of
purity yield
(%)
photoirradiation wavelength
reaction conditionsa
[
11C]O (%)
(%)b
labeled product
300-400 nm
full spectrum
40 °C, hν 300-400 nm, 6 min 40 s
60 °C, hν 300-400 nm, 5 min
90 °C, hν full spectrum, 6 min 40 s
40 °C, hν 300-400 nm, 6 min 40 s
and TBAOH 0.5 equiv
4
7
29
80
84
92
97
84
3
6
28
67
[1-11C]pentanoic acid
7
2
7
18
11
16
64
[1-11C]nonanoic acid
[1-11C]tridecanoic acid
[1-11C]4-phenylbutyric acid
58
a Temperature, photoirradiation wavelength, reaction time.
b Decay-corrected radiochemical yield determined by LC.
a Reaction conditions: THF/H2O 4:1, 60 °C, reaction time 5 min.
TABLE 4. Effect of Reaction Conditions on
Radiochemical Yield of [1-11C]tridecanoic Acida
tion, and electron-transfer reactions. Water, as a protic
solvent, is capable of forming the hydrogen bond to the
carbonyl group, thus decreasing the activation energy for
decarbonylation15 and acylation.
convn of
purity
(%)
yield
(%)b
reaction conditions
[1-11C]O (%)
60 °C, hν full spectrum
30 °C, hν full spectrum
30 °C, hν 300-400 nm
80
83
82
84
84
91
67 (49)
70 (51)
75 (58)
The optimization of the synthesis was attempted using
3-phenyliodopropane as a model substrate. Initial experi-
ments showed that the higher the ratio of water to
organic solvent in the mixture, the higher the purity of
the crude product. On the other hand, the iodides are
less soluble in systems of high water content. For
3-phenyliodopropane and more hydrophilic iodides, sev-
eral water-miscible solvents were suitable (Table 1);
however, for more hydrophobic long-chain iodides the
miscibility of reactants became a key factor, and the
THF-water solvent system was found to be the most
convenient.19 In seeking general reaction conditions for
the labeling of carboxylic acids, the effects of temperature,
reaction time, photoinitiation parameters, additives, and
bases were examined.
a Reaction conditions: THF/H2O 4:1, reaction time 5 min,
TBAOH 0.3 equiv. b Decay-corrected radiochemical yield deter-
mined by LC; isolated decay-corrected radiochemical yields are
shown in parentheses.
of [11C]carbon monoxide, several syntheses of tridecanoic
[11C]acid were performed at elevated temperatures and
using the full spectrum of the UV lamp. Despite increased
consumption of alkyl iodides, the yields of the labeled acid
were still low (Table 3). The most effective way to improve
the yield was to add 0.5 equiv of tetrabutylammonium
hydroxide (TBAOH) to the reactant mixture (Table 3).
The optimal amount of TBAOH that provided the
highest radiochemical yields of [1-11C]tridecanoic acid
was determined to be approximately 0.3-0.4 equiv.
Further increase in the amount of TBAOH over 0.6-0.8
equiv led to a decline in the purity of the crude product
and an overall decrease in the radiochemical yield. For
labeling reactions assisted with TBAOH, radiochemical
yields were nearly independent of temperature and
photoirradiation wavelength (Table 4).
Apart from TBAOH, several other bases were inves-
tigated. Amine bases (triethylamine, N-methylmorpho-
line, and DMAP) did not improve the synthesis (Table 5,
entries 1, 2, and 7). Conversion of [11C]carbon monoxide
increased at the expense of side reactions, while yields
of labeled acids actually decreased. Of several inorganic
bases, potassium hydroxide was the one that had a
positive effect comparable to that of TBAOH.20
Furthermore, it was also observed that yield was not
significantly influenced by acidity, even when the acidity
of the medium increased, approaching pH 2 (Table 5,
entry 6).
The impact of photoirradiation intensity was also
investigated. For the series of labeling syntheses of
[carboxyl-11C]isobutyric acid promoted with TBAOH,
yield increased and reached a plateau at approximately
half the maximum output of the UV light source and
remained constant afterward. The purity of the crude
product was 96 ( 2% in all the experiments.
The decay-corrected radiochemical yields of [11C]4-
phenylbutyric acid were in the 60-70% range in the
temperature interval between 35 and 95 °C, dropping to
40% when the temperature decreased to 25 °C. The
difference in yield was related only to the conversion of
[11C]carbon monoxide, while the purity of the crude
product was 85 ( 2% in all the experiments.
Reaction time is an important parameter in the practi-
cal preparation of compounds labeled with short-lived
radionuclides. Overlong reactions are not productive and
result in decreased radiochemical yield and specific
radioactivity of the labeled compound. The optimal
reaction time for the labeling of [1-11C]-4-phenylbutyric
acid was approximately 5-6 min, as determined experi-
mentally11 from the plot of radiochemical yield (in this
case not corrected for radioactive decay) versus time.
Attempts to obtain comparable radiochemical yields in
synthesizing acids from several unfunctionalized ali-
phatic iodoalkanes, employing the same reaction condi-
tions as for 1-iodo-3-phenylpropane, unexpectedly failed.
Under pH-neutral conditions, the carbonylation of simple
alkyl iodides gave distinctly lower yields than did the
carbonylation of 1-iodo-3-phenylpropane (Table 2). Evi-
dently the behavior of 1-iodo-3-phenylpropane differs
from that of the alkyl iodides that do not contain phenyl
substituent.
A possible reason for this could be differences in the
photochemistry of the iodides. To increase the conversion
A number of compounds were labeled using the devised
reaction conditions (Table 6). Mixed solvents provided
suitable reaction media for carrying out the radical-
mediated carboxylation of both short- and long-chain
primary alkyl iodides (Table 6, entries 3, 8, and 9).
(19) Compared to other organic solvents examined, THF solutions
of iodohexadecane, the most lipophilic of the studied substrates, were
capable of incorporating the greatest amounts of water. This solvent
mixture was also capable of dissolving small amounts of inorganic
additives while retaining its homogeneity.
2246 J. Org. Chem., Vol. 70, No. 6, 2005

Radical Carboxylation of Alkyl Iodides with 11CO
TABLE 5. Effect of Additives on Radiochemical Yield of [1-11C]4-Phenylbutyric Acida
organic
solvent
convn of
purity
(%)
yield
(%)b
entry
additive, amount (mmol)
[
11C]O (%)
Nc
1
2
3
4
5
6
7
8
triethylamine, 0.18
N-methylmorpholine, 0.18
KOH, 0.05
THF
THF
THF
THF
ACN
ACN
ACN
ACN
76 ( 1
62
19 ( 1
46
14 ( 1
29
2
1
2
2
2
2
2
2
75 ( 6
81 ( 1
71 ( 1
45 ( 3
53 ( 3
58 ( 4
85 ( 4
83 ( 1
84 ( 4
90 ( 11
58 ( 9
23 ( 16
63 ( 5
48 ( 2
61 ( 4
41 ( 2
34 ( 11
13 ( 8
TBAOH, 0.05
KOH, 0.05
acetic acid, 0.33
DMAP, 0.05
TBAF, 0.05
a Reaction conditions: organic solvent/H2O 4:1, 30 °C, photoirradiation 300-400 nm, reaction time 6 min 40 s. b Decay-corrected
radiochemical yield determined by LC. c Number of runs.
TABLE 6. Radiochemical Yields for 11C-Labeled Acids
a The position of the 11C label is denoted by an asterisk. b Decay-corrected radiochemical yield determined by LC. c Number of runs.
d Unseparated peaks.
Secondary alkyl iodides gave slightly higher radio-
chemical yields than did primary ones (Table 6, entries
1, 2, 3, 8, and 9); however, the carboxylation of tert-butyl
iodide could not be accomplished (Table 6, entry 6).
Though a trace with a retention time matching that of
labeled 2,2-dimethylpropionic acid was detected on an
analytical HPLC chromatogram, the product could not
be isolated for further characterization. On the other
hand, 1-iodoadamantane could be efficiently carboxylated
(Table 6, entries 11a-c). This difference may be explained
by the dissimilar ability of the two iodides to participate
in the side reactions that proceed via carbocation inter-
mediates, such as solvolysis, elimination, and electron
transfer.21 The rigid structure of adamantane precludes
the formation of the strained bridgehead cation, whereas
the tert-butyl cation is easily formed. According to our
J. Org. Chem, Vol. 70, No. 6, 2005 2247

Itsenko and Långstro¨m
observations the amounts of the iodide consumed in the
reactions were much higher in the case of tert-butyl
iodide.
the rapid synthesis of [1-11C]carboxylic acids. This method
offers an alternative synthetic route to [carboxyl-11C]-
compounds, and therefore may be of value in view of
several advantages it offers: i.e., high (50-70%) decay-
corrected radiochemical yields of 11C-labeled acids and
high (80-90%) conversion of [11C]carbon monoxide were
achieved in short (5-7 min) reaction times. Organic
solvent-water mixtures provide an equally suitable
reaction medium for carboxylating short- and long-chain
alkyl iodides. The functional groups that are not compat-
ible with other labeling methods (e.g., Grignard) are
tolerated; therefore protection-deprotection may not be
required. As a one-step, one-pot procedure, it is suitable
for rapid synthesis employing short-lived nuclides. The
reaction media is compatible with subsequent purifica-
tion by means of preparative HPLC. Organic iodides,
used as starting materials, do not trap the stable-isotope
counterpart of the labeling precursor (carbon monoxide
in this case) from the atmosphere during storage, and
therefore do not contribute to the isotopic dilution of
labeled products. Investigation of the observed reactivity
patterns and the effect of acetone is currently in progress.
To increase the solubility of iodohexadecane, the most
lipophilic of the used iodides, the water fraction in the
solvent mixture (THF-water) was reduced from 1/4 to
1/10 (Table 6, entry 9).
[1-11C]1,10-Decanedicarboxylic acid was prepared un-
der basic conditions (Table 6, entry 10). Labeling this
compound via Grignard synthesis would require several
steps, including the protection of the carboxylic group in
the precursor.
The carboxylation of 5-iodo-1-pentene (Table 6, entry
7) gave a complex mixture of labeled products. The
carboxylation of 4-(3-iodopropyl)phenol resulted in very
low yields (Table 6, entry 5). Interestingly, the addition
of phenol or 4-ethylphenol to the reactant mixture in
preliminary test experiments had virtually no effect on
the synthesis of 4-phenylbutyric [11C]acid from (3-iodo-
propyl)benzene.
In the end, we found that a ternary THF-acetone-
water system may be a better alternative, because similar
yields were achieved under nonbasic conditions (Table
6, entries 9a vs 9b). As noted above, irradiation with the
full light spectrum of the lamp, and under the same
reaction conditions (i.e. using the THF-water system as
solvent), led to no effect of comparable magnitude. These
observations may indicate that acetone can act as a
triplet sensitizer.22 Should this be so, intersystem cross-
ing in alkyl-substituded benzenes may account for the
higher yields of [1-11C]4-phenylbutyric acid than of the
saturated [11C]unsubstituted acids. This observation
encouraged us to undertake more thorough investigation
of the phenomenon.
Experimental Section
[11C]Carbon dioxide production was performed using a
Scanditronix MC-17 cyclotron at Uppsala Imanet. The 14N-
(p,R)11C reaction was employed in a gas target, containing
nitrogen (Nitrogen 6.0) and 0.1% oxygen (Oxygen 4.8), that
was bombarded with 17 MeV protons. [11C]Carbon monoxide
was obtained by reducing [11C]carbon dioxide as described
previously.13 Liquid chromatographic analysis (LC) was per-
formed with a gradient pump and a variable-wavelength UV
detector in series with a â+-flow detector. An automated
synthesis apparatus, Synthia,23 was used for LC purification
of the labeled products. Radioactivity was measured in an ion
chamber. A xenon-mercury lamp was used as a photoirra-
diation source. In analyzing the 11C-labeled compounds, iso-
topically unchanged reference substances were used for com-
parison in all LC runs. NMR spectra were recorded at 400 MHz
for 1H and at 100 MHz for 13C, at 25 °C. Chemical shifts were
referenced to residual protons in solvents (CDCl3: 7.26 ppm;
DMSO-d6: 2.50 ppm) in proton spectra and to solvent signals
(CDCl3: 77.00 ppm; DMSO-d6: 39.52 ppm) in carbon spectra.
LC-MS analysis was performed using electrospray ionization
(ESI-).
Radiochemical purity of the labeled compounds after
LC purification was in the range of 97-99%.
To verify the labeling position, carboxyl-13C-substituted
4-phenylbutyric acid was synthesized using (13C)carbon
monoxide together with [11C]carbon monoxide. The reac-
tion was performed as 11C-labeling. The identity of the
compound and the labeling position were confirmed by
1
the H and 13C NMR experiments.
Specific radioactivity is an important quality of 11C-
labeled compounds used as PET tracers. For example,
3.19 GBq of [1-11C]1,10-decanedicarboxylic acid was
obtained with specific radioactivity of 188 GBq/µmol
within 35 min of the end of 10 µA bombardment.
Solvents: THF was distilled under nitrogen from sodium/
benzophenone; all other solvents were commercial grade. The
solvents were purged with helium before use.
The alkyl iodides were commercially available or otherwise
prepared from commercial alkyl bromides via the Finkelstein
reaction.
Conclusions
Preparation of [carboxyl-11C]Acids. General Proce-
dure. An iodide (100 µmol) was placed in a capped vial (1 mL,
flushed beforehand with nitrogen to remove oxygen) and
dissolved in THF (400 µL). Water (100 µL) and an optional
additive were added to the solution ca. 7 min before the start
of synthesis. The resulting mixture was pressurized (over 40
MPa) in a microautoclave (270 µL) that was pre-charged with
[11C]carbon monoxide (10-8-10-9 mol) mixed with He. The
mixture was irradiated with a UV source for 5-7 min while
stirring at 35 °C. The crude reaction mixture was then
transferred from the autoclave to a capped vial held under
reduced pressure. After measuring the radioactivity, the vial
was purged with nitrogen and the radioactivity measured
again. The crude product was diluted with acetonitrile or
methanol (0.6 mL) and injected on the semipreparative LC.
Analytical LC and LC-MS were used to assess the identity and
radiochemical purity of the collected fraction.
Photoinitiated free-radical carboxylation of primary,
secondary, and in some cases tertiary alkyl iodides with
[11C]carbon monoxide has been developed and applied in
(20) TBAOH was more convenient than KOH due to its higher
solubility in mixed solvents. The addition of KOH to mixed solvents
often resulted in separation of two liquid phases, formation of stable
emulsions, and precipitation of reactants. The emulsions were also
suitable for labeling synthesis, though they gave less reproducible
results. With short-chain (more hydrophilic) iodides, when more water-
rich solvent mixtures could be employed, KOH was used without
noticeable complications (Table 6, entry 2).
(21) Kropp, P. J.; Adkins, R. L. J. Am. Chem. Soc. 1991, 113, 2709-
2717.
(22) Photochemical Key Steps in Organic Synthesis: An Experimental
Course; Mattay, J., Griesbeck, A. G., Eds.; VCH: Weinheim, Germany,
1994; p 5.
2248 J. Org. Chem., Vol. 70, No. 6, 2005

Radical Carboxylation of Alkyl Iodides with 11CO
(1-13C)4-Phenylbutyric acid24 was synthesized from (3-
iodopropyl)benzene as described in the general procedure.
(13C)Carbon monoxide (approximately 0.05 mmol) was added
tracted with ether. The extract was washed successively with
concentrated water solutions of Na2S2O3 and Na2HCO3. The
ethereal solution was dried over MgSO4 and evaporated at
reduced pressure to yield 531 mg (94%) of colorless oil. 1H NMR
(400 MHz, CDCl3): δ 7.06 (m, 2H), 6.78 (m, 2H), 4.80 (br s,
1H), 3.16 (t, 2H), 2.66 (t, 2H), 2.09 (tt, 2H). 13C NMR (100 MHz,
CDCl3): δ 153.8, 132.6, 129.7, 115.3, 35.2, 35.0, 6.4.
11-Iodoundecanoic acid28 and 5-iodo-1-pentene29 were
prepared via the Finkelstein reaction from the corresponding
bromides.
1
to [11C]carbon monoxide and the reaction was run for 1 h. H
NMR (400 MHz, CDCl3): δ 10.0 (br s, 1H), 7.35-7.18 (m, 5H),
2
3
13
13
2.70 (m, 2H), 2.41 (m, JH ) 7.3 Hz, 2H), 2.00 (m, JH
)
C
C
4.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 180.5, 141.2, 128.5,
2
1
13 13
13 13
128.4, 126.0, 34.9 (d, J
C ) 3.8 Hz), 33.0 (d, J
C ) 55.5
C
C
Hz), 26.2.
4-(4-Hydroxyphenyl)butyric acid25 was prepared via
demethylation of 4-(4-methoxyphenyl)butyric acid by boron
tribromide.26 1H NMR (400 MHz, DMSO-d6): δ 11.96 (br s,
1H), 9.12 (br s, 1H), 6.96 (m, 2H), 6.67 (m, 2H), 2.46 (t, 2H),
2.18 (t, 2H), 1.73 (tt, 2H). 13C NMR (100 MHz, DMSO-d6): δ
174.3, 155.4, 131.5, 129.1, 115.0, 33.6, 33.0, 26.6.
Acknowledgment. We thank Dr. Tor Kihlberg and
Dr. Pernilla Fra¨ndberg for valuable discussions and
Tommy Ferm for his technical assistance. The Swedish
Research Council is acknowledged for its support through
Grant No 621-2003-2855 (B.L.).
4-(3-Iodopropyl)phenol.27 4-(3-Hydroxypropyl)phenol (330
mg) was stirred with hydroiodic acid (47%, 10 mL) at 100 °C
overnight. The reaction mixture was allowed to cool and then
poured into water (20 mL). The resulting mixture was ex-
Supporting Information Available: The 13C NMR spec-
tra of the following compounds, prepared for use as labeling
precursors or references: 4-(4-hydroxyphenyl)butyric acid,
4-(3-iodopropyl)-phenol, 5-iodo-1-pentene, and 11-iodoun-
decanoic acid. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) Bjurling, P.; Reineck, R.; Westerberg, G.; Gee, A. D.; Sutcliffe,
J.; Långstro¨m, B. In Proceedings of the VIth workshop on targetry and
target chemistry; TRIUMF: Vancouver, Canada, 1995; pp 282-284.
(24) Wempe, M. F.; Grunwell, J. R. J. Org. Chem. 1995, 2714-2720.
(25) Defauw, J. M.; Murphy, M. M.; Jagdmann, G. E.; Hu, H.;
Lampe, J. W.; Hollinshead, S. P.; Mitchell, T. J.; Crane, H. M.;
Heerding, J. M.; Mendoza, J. S.; Davis, J. E.; Darges, J. W.; Hubbard,
F. R.; Hall, S. E. J. Med. Chem. 1996, 5215-5227.
(26) McOmie, J. F. W.; Watts, M. L.; West, D. E. Tetrahedron 1968,
2289-2292.
(27) Cheng, C.-S.; Ferber, C.; Bashford, R. I., Jr.; Grillot, G. F. J.
Am. Chem. Soc. 1951, 73, 4081-4084.
JO047806S
(28) Matsuyama, H.; Nakamura, T.; Kamigata, N. J. Org. Chem.
1989, 24, 5218-5223.
(29) Snider, B. H.; Hawryluk, N. A. Org. Lett. 2001, 3, 569-572.
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