Carboxylation of alkyl iodides with [11C] and ( 13C)carbon monoxide: Using sulfoxides as oxygen nucleophiles

Article abstract of DOI:10.1055/s-2005-922751

¹¹C-Labeled carboxylic acids were prepared from alkyl iodides and [¹¹C]carbon monoxide by irradiation by UV light in anhydrous DMSO solutions in the presence of triethylamine. Sulfoxides other than DMSO can be used and may be used in

Full text of DOI:10.1055/s-2005-922751

3154
LETTER
Carboxylation of Alkyl Iodides with [11C] and (13C)Carbon Monoxide:
Using Sulfoxides as Oxygen Nucleophiles
Sulfoxides as
Oxy
l
genN
u
e
cleophile
s
in
Radical Ca
s
rbonylatio
i
n
y Itsenko,a Tor Kihlberg,b Bengt Långström*a,b
a
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 599, 751 21 Uppsala, Sweden
b
Uppsala Imanet AB, Box 967, 751 09 Uppsala, Sweden
Fax +46(18)666819; E-mail: bengt.langstrom@uppsala.imanet.se
Received 13 October 2005
as a nucleophile may be improved by using hydroxide an-
ion. However, the strong base promotes side reactions,
like elimination and nucleophilic substitution. It is often
the case that these side reactions are not problematic in
11C-synthesis, because other reactants are used in a large
excess to [11C]carbon monoxide.11 More demanding are
the larger-scale applications, e.g. with (13C)carbon mon-
oxide, which is more practical to use in stoichiometric
amounts with respect to other reactants.
Abstract: 11C-Labeled carboxylic acids were prepared from alkyl
iodides and [11C]carbon monoxide by irradiation by UV light in an-
hydrous DMSO solutions in the presence of triethylamine. Sulf-
oxides other than DMSO can be used and may be used in
stoichiometric amounts using inert solvents.
Key words: sulfoxides, radical reactions, carbonylations, carboxy-
lic acid, photochemistry
Biologically active organic compounds labeled with sta-
ble and radioactive carbon isotopes have found broad ap-
plication as tracers in biochemical studies. In particular,
compounds labeled with short-lived 11C (t1/2 = 20.3 min)1
are used in positron emission tomography (PET), a nucle-
ar medicine technique for molecular imaging in vivo.2
The increasing use of PET in clinical practice,3 drug de-
velopment,4 and biomedical research has stimulated the
development of new labeling strategies.5 11C is produced
using particle accelerators and is available in a few simple
chemical forms.6 Furthermore, the short half-life of 11C
seriously restricts the scope of the synthetic methods ap-
plicable to 11C-labeling.7
Here we report that DMSO and other sulfoxides may be
advantageously used as nucleophiles in radical carbonyla-
tion for the synthesis of 11C- and 13C-labeled carboxylic
acids. The method benefits from the orthogonal reactivity
of sulfoxides towards alkyl and acyl halides thereby
avoiding the side reactions caused by strong bases. The
high reactivity of DMSO and other sulfoxides toward acid
halides is known: sulfoxides operate as oxygen nucleo-
philes to produce acids.12
11C-Labeled carboxylic acids were prepared from alkyl
iodides and [11C]carbon monoxide by irradiation with UV
light in anhydrous DMSO solutions in the presence of tri-
ethylamine (Scheme 1). The reaction proceeds rapidly at
ambient temperature (30–35 °C) providing high conver-
sion of [11C]carbon monoxide and high radiochemical
yields in a short reaction time (6 min; Table 1). The addi-
tion of triethylamine was essential; however, the exact
role of triethylamine is not yet clear.13 Neither water as a
source of hydroxyl group nor the use of strong bases was
required.
The carboxylic functional group is frequently found in
bioactive molecules and may be conveniently labeled via
the carboxylation of a Grignard reagent using cyclotron-
produced [11C]carbon dioxide.8 The labeling of function-
alized acids, however, may become difficult due to the re-
activity of Grignard reagents. An alternative approach is
radical carbonylation9 of organoiodides using [11C]carbon
monoxide as a labeling precursor.10
The radical carbonylation reaction is based on the favor-
able combination of several radicals and a final ionic
step.9b The formation of an acyl iodide intermediate in a
sequence of radical steps is considered as reversible and
endothermic.9b The trapping of the acyl iodide with a nu-
cleophile, resulting in the formation of a stable product in
the ionic step, serves as the driving force for the reaction.
Me
Me
O
UV
*
RI
+
*CO
+
O
S
R
C
Et3N
OH
R = alkyl
*C = 11
C
Scheme 1
Less reactive nucleophiles lead to longer reaction times The reactivity of DMSO in radical carbonylation is higher
with unlabeled carbon monoxide9b and decrease the ra- than that of alcohols or water but less than the reactivity
diochemical yields in reactions with [11C]carbon monox- of alkyl amines. In fact, DMSO has been used as a solvent
ide,10b due to competing radioactive decay. The for carrying out carbonylation employing [11C]carbon
radiochemical yields in the labeling of acids using water monoxide with amine nucleophiles.10a The analysis of the
data confirmed that in the former case the reactions gave
[11C]acids as byproducts, with the yields dependent on the
SYNLETT 2005, No. 20, pp 3154–3156
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922751; Art ID: G33605ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5
reactivity of the amines. With alcohol nucleophiles the
[11C]acids were the major products (over 80%). Hence

LETTER
Sulfoxides as Oxygen Nucleophiles in Radical Carbonylation
3155
Table 1 Yields of Labeled Acids
Entry
Product
Sulfoxide/Solvent
DMSO
Conversion COa,d (%)
Purityb,d (%)
Yieldc,d (%)
1
2
[1-11C]4-Phenylbutyric acid
84
67
74
70
62 4
47 7
Dibutylsulfoxide,
(1.0 mmol)/THF
3
4
Dibutylsulfoxide,
(0.1 mmol)/THF
76
79
35
85
27e
[1-11C]Cyclohexane
carboxylic acid
DMSO
67 3
5
6
7
DMSO–THF (9:1)
DMSO–THF (1:1)
DMSO
76
81
2
86
76
60
65 3
64 3
ca. 1
[1-11C]Heptadecanoic acid
[1-11C]2,2-Dimethylpropionic
acid
8
9
[1-11C]2-Propylpentanoic acid
DMSO
DMSO
84
79
89
49
75 1
39 4
[1-11C]4-(4-Hydroxyphenyl)
butyric acid
a Conversion: based on reacted [11C]carbon monoxide.
b Radiochemical purity of the product.
c Decay-corrected radiochemical yield determined by HPLC.
d Average over 2–4 runs.
e Single run.
DMSO may be placed between amines and alcohols in Sulfoxides and triethylamine are highly hygroscopic com-
ranking the reactivity of the nucleophiles in radical carbo- pounds. Though anhydrous reagents were employed in the
nylation.
syntheses, the presence of small amounts of water could
not be excluded. Water may potentially be the nucleo-
philic reactant; however, the following observations point
to the conclusion that the source of carboxyl oxygen in the
products is the sulfoxide: (a) the addition of methanol as a
competing nucleophile does not give a rise to labeled
methyl ester; (b) the yields of acids using water–organic
solvent (other than DMSO) in the presence of triethyl-
amine were much lower; and (c) DMSO and less polar
sulfoxides may be used as reagents in an inert solvent
(Table 1, entries 2, 3 and 5).
Radiochemical yields in radical carbonylation increase
with the polarity of the solvent;10a thus the high polarity of
DMSO makes it a superior reaction media. On the other
hand, the solubility of long-chain alkyl iodides in this sol-
vent is poor. In such cases THF may be used as a co-sol-
vent (Table 1, entries 5 and 6). Other sulfoxides have the
same reactivity pattern and may also be used, for example,
dibutyl sulfoxide (Table 1, entry 2). DMSO may be pre-
ferred, because it can be easily separated from the radio-
labeled product using reversed-phase preparative HPLC.
To summarize, the free radical carboxylation of alkyl io-
dides using carbon monoxide and sulfoxides as oxygen
nucleophiles is a simple procedure for the preparation of
11C-labeled and 13C-substituted compounds under mild
conditions.
Owing to the high reactivity of sulfoxides this method was
useful with iodide substrates that gave poor results using
the previously described approach, for example, [1-11C]4-
(4-hydroxyphenyl)butyric acid was obtained from 4-(3-
iodopropyl)phenol in 39% yield (Table 1, entry 9). Previ-
ously, using aqueous basic conditions no product could be
detected. The labeling of pivalic acid gave a low yield
(Table 1, entry 7).
All reactions were performed in a 270 mL stainless steel batch-type
reactor fitted with a sapphire window.15 The photoirradiation from
a xenon lamp (L8253, Hamamatsu Photonics) was supplied into the
reactor through the window using a light guide.
The orthogonal reactivity of sulfoxides in nucleophilic
substitution reactions at sp3- and sp2-carbons makes it
possible to transfer this method to a synthesis using 13C-
substituted and isotopically unmodified carbon monox-
ide. In one reaction (13C)carbon monoxide was used to-
gether with [11C]carbon monoxide, which resulted in the
synthesis of (13C)4-phenylbutyric acid in 25% yield.14
Typical Procedure
Et3N (25 mL, 0.18 mmol) and alkyl iodide (0.1 mmol) were dis-
solved in DMSO or DMSO–organic solvent (450 mL) and trans-
ferred into an autoclave charged with [11C]carbon monoxide. Then
the contents of the reactor was pressurized to ca. 40 MPa and irra-
diated with the xenon lamp using an optical filter in the range 280–
400 nm. After 6 min the reactor was discharged into a collection vial
and purified using LC.
Synlett 2005, No. 20, 3154–3156 © Thieme Stuttgart · New York

3156
O. Itsenko et al.
LETTER
The labeled compounds were identified in the reaction mixture us-
ing HPLC and were referenced to identical isotopically unmodified
compounds. Furthermore, the products were characterized using
LCMS. The labeling position was confirmed via NMR spectrosco-
py of the (13C)4-phenylbutyric acid, obtained using a mixture of
(13C)- and [11C]carbon monoxide.
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Acknowledgment
Financial support from Amersham Fund, Uppsala University and
Swedish Science Research Council are gratefully acknowledged.
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Synlett 2005, No. 20, 3154–3156 © Thieme Stuttgart · New York