CuI-Catalyzed 11C carboxylation of boronic acid esters: A rapid and convenient entry to 11C-labeled carboxylic acids, esters, and amides

Article abstract of DOI:10.1002/anie.201107263

Rapid and direct: The carboxylation of boronic acid esters with ¹¹CO₂ provides [¹¹C]carboxylic acids as a convenient entry into [¹¹C]esters and [¹¹C]amides (see scheme). This conversion of boronates is tolerant to diverse functional groups (e.g., halo, nitro, or carbonyl). Copyright

Full text of DOI:10.1002/anie.201107263

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Angewandte
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DOI: 10.1002/anie.201107263
Radiochemistry
CuI-Catalyzed 11C Carboxylation of Boronic Acid Esters: A Rapid and
Convenient Entry to 11C-Labeled Carboxylic Acids, Esters, and
Amides**
Patrick J. Riss,* Shuiyu Lu, Sanjay Telu, Franklin I. Aigbirhio, and Victor W. Pike
Noninvasive imaging with positron emission tomography
(PET) allows for quantitative studies of radiotracer distribu-
tion in living subjects and is increasingly used in routine
clinical diagnosis, preclinical and clinical-phase drug develop-
ment, and biomedical research. Novel radiotracers for imag-
ing a variety of biological targets are continually needed to
fully exploit the potential of PET. Consequently, the existence
of reliable chemical methods for labeling organic molecules
with short-lived positron emitters is key to the production of
novel radiotracers intended for complex imaging studies in
humans.[1,2]
Scheme 1. Radiosynthesis of [11C]carboxylic acids from 11CO2 and
classical organometallic reagents or boronic acid esters.
care, including diligent control of reagent stoichiometry, and
the exclusion of moisture and atmospheric CO2. Moreover,
these methods are limited with respect to the structural
diversity of products that may be obtained. Recently, interest
in the direct incorporation of 11CO2 into radiotracers has been
revived by Hooker et al. and Wilson et al. who elaborated
novel carboxylation methods for the synthesis of 11C-labeled
carbamates and ureas.[5] Such direct incorporation of 11C into
candidate radiotracers is attractive with regard to avoiding
losses of radioactivity, conserving specific radioactivity, and
achieving rapid and simple radiosyntheses.
11C, despite its short half-life (t1/2 = 20.4 min), is a valuable
radiolabel for PET radiotracers because carbon is present in
nearly all biochemicals and drug candidates.[2,3] Isotopic
substitution of 12C with 11C represents an often elegant and
desirable approach in radiotracer development. The isotope
11C is readily obtained in high activity and high specific
radioactivity from moderate-energy cyclotrons by the 14N-
(p,a)11C nuclear reaction.[2] Irradiation of nitrogen gas in the
presence of oxygen produces [11C]carbon dioxide, whereas
irradiation in the presence of hydrogen produces
[11C]methane. The direct use of these two primary precursors
for radiolabeling has, however, been quite limited. Instead,
major effort has been expended on converting these pre-
cursors into 11C-labeling agents with more versatile reactivity.
For example, most 11C-labeled radiotracers are obtained by
alkylation of heteroatom nucleophiles with 11CH3I or
11CH3OTf.[2]
Within our radiotracer development programs, we sought
an efficient method for producing [11C]carboxylates that
might display high functional-group tolerance. Unlike orga-
nolithium and Grignard reagents, boronic acid esters are quite
stable to air and moisture and therefore are easily handled
and stored. Moreover, organolithium and Grignard reagents
can only be formed from molecules devoid of reactive
electrophilic functional groups, whereas boronic acid esters
can be readily introduced into highly functionalized mole-
cules.[6] In view of these considerations and of recent
developments in transition metal-mediated carboxylation
reactions,[7–9] in particular with copper–bisoxazoline[8] and
copper N-heterocyclic carbene (Cu-NHC)[9] type catalysts, we
Direct applications of 11CO2 in radiotracer synthesis are
mostly 11C carboxylations of Grignard and organolithium
reagents to produce 11C-labeled carboxylic acids (Scheme 1,
top).[4] For successful outcomes, these reactions require great
succeeded in devising a new catalytic method for C 11C bond
À
[*] Dr. P. J. Riss, Dr. F. I. Aigbirhio
formation direct from 11CO2 using boronic acid esters, as we
now report herein (Scheme 1, bottom).
Wolfson Brain Imaging Centre, University of Cambridge
Box 65 Addenbrooke’s Hospital, CB2 0QQ, Cambridge (UK)
E-mail: pr340@wbic.cam.ac.uk
First, we tried to optimize the trapping agent/complex
ligand. In non-radioactive chemistry, carboxylation reactions
are generally carried out with super-stoichiometric amounts
of CO2 at atmospheric pressure where low solubility of CO2 in
liquid reaction media is not an obstacle, since the dissolved
CO2 is in continuous equilibrium with that in the gas phase.
We hypothesized that the diffusion of CO2 into the liquid
phase is often the rate-limiting step because reaction times
can be remarkably decreased when the reaction is conducted
at elevated pressure, as for example in the Kolbe–Schmitt
synthesis of salicylic acid.[10] However, in the case of no-
carrier-added (n.c.a.) 11C radiochemistry, only a trace amount
Dr. P. J. Riss, Dr. S. Lu, Dr. S. Telu, Dr. V. W. Pike
Molecular Imaging Branch, National Institute of Mental Health,
Bldg 10 Room B3C346A
10 Center Drive, Bethesda, MD 20892-1003 (USA)
[**] P.J.R. was supported by a Medical Research Council (UK) post-
doctoral fellowship as a visiting volunteer worker at the NIH. S.T.,
S.L., and V.W.P. were supported by the Intramural Research
Program of the NIH (NIMH). We thank Jinsoo Hong (NIMH) for
technical assistance and the NIH Clinical PET department (Chief,
Dr. P. Herscovitch) for 11C production.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107263.
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(< 1 mmol) of [11C/12C]CO2 is present in the stream of inert
carrier gas and hence the partial pressure of 11CO2 is very low.
Consequently, the amount of 11CO2 dissolved in solution is
also very low in accord with Henryꢀs law, even within
a pressurized reaction vessel. To overcome this issue, the
11CO2 needs to be held in solution whilst preserving its
reactivity. In earlier studies strongly basic imines, such as 1,8-
diazabicyclo[5.4.0]undecene (DBU) or phosphazene bases,
have been used to retain 11CO2 in solution.[5] We turned our
attention to similar compounds which in addition to being
basic might also chelate metal ions or act as complex ligands
that can promote the carboxylation reaction.
We aimed initially to discover a simple metal salt–ligand
system capable of mediating the carboxylation reaction while
simultaneously retaining a high proportion of delivered 11CO2
in solution. As a model reaction, we chose to use phenyl-
boronic acid 1,3-propanediol ester (1a; ca. 60–70 mmol), CuI
catalyst, and CsF in a 1:1:3 molar ratio in dimethylformamide
(DMF; 0.4 mL). In a control experiment omitting base/ligand,
11CO2 trapping efficiency was low and no [11C]-1b was
obtained (Table 1, entry 1). Other bases improved the trap-
ping efficiency without giving useful yields of [11C]-1b
(Table 1, entries 2–9). As expected, the published catalytic
Cu-NHC ligand mixture[9] also trapped 11CO2 exceedingly
well. However, only trace amounts of [11C]-1b were formed
(Table 1, entry 9), presumably because radioactivity became
trapped as unreactive tBuO11CO2K.
Bisoxazolines also gave efficient trapping, although only
low yields of [11C]-1b were obtained after 10 min at 908C
(Table 1, entries 10 and 11).[8] The low yields were attributed
to loss of 11CO2 from the reaction mixture at elevated
temperature. Therefore, we turned our attention to using
a combination of one of the efficient trapping agents, DBU,
with a bisoxazoline ligand (Table 1, entry 12). This gave an
increased yield of [11C]-1b, but with suboptimal trapping
efficiency. Further screening of ligand–catalyst combinations
(Table 1, entries 13 and 14) revealed TMEDA to be out-
standingly effective with regard to 11CO2 trapping efficiency.
The second step was to vary the copper catalyst source.
We tested whether CuI was the preferred source by changing
the copper salt in the promising reaction example that used
TMEDA/CuI (Table 2, entry 1). Reaction did not occur when
Table 2: Effects of the copper catalyst and MF on the RCY of [11C]-1b.[a]
Entry
Catalyst
MF
RCY [%]
1
2
3
4
5
6
7
8
9
10
CuI
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
none
none
49
–
13
24
36
9
none
CuCl
CuBr
CuCN
CuOTf
Cu0[b]
CuF2
CuF2
CuI
3
[c]
trace
9
–
[a] Conditions: DMF (400 mL), 1a (50 mmol), TMEDA (100 mm), catalyst
(2 mmol), CsF (150 mmol), 908C, 10 min. [b] Finely ground copper
powder. [c] In the presence of ascorbic acid (100 mm).
Table 1: Effect of the base/ligand on the 11CO2 trapping efficiency and the
decay-corrected radiochemical yield of [11C]-1b.
CuI was omitted (Table 2, entry 2). Equimolar replacement of
CuI with CuCl, CuBr, CuCN, or CuOTf did not improve the
radiochemical yield (Table 2, entries 3–6). Also Cu0 (Table 2,
entry 7) was less effective than CuI. Attempted generation of
CuI in situ from CuF2 and ascorbic acid gave only trace
amounts of [11C]-1b (Table 2, entry 8), probably due to the
low stability of CuF which disproportionates immediately to
yield Cu0 and CuF2.[11] Therefore CuI was established as the
preferred copper source.
Third, we studied the effect of the fluoride ion source and
the solvent. We observed that omission of CsF resulted in low
or no yield of [11C]-1b (Table 2, entries 9 and 10). We
considered that higher concentrations of fluoride ion might
prove beneficial. In order to circumvent the limited solubility
of CsF in DMF, we turned our attention to more soluble
sources of fluoride ion. The use of tetrabutylammmonium
fluoride (TBAF; Table 3, entry 2) or [18]crown-6 (18C6) with
either KF (Table 3, entry 3) or CsF (Table 3, entry 4) gave no
improvement over the use of CsF alone (Table 3, entry 1).
However, the use of crypt-222 in conjunction with KF under
homogeneous conditions led to remarkable improvements in
the carboxylation yields (Table 3, entries 5–9). Thus, the
combination of CuI, KF, crypt-222, and TMEDA after
10 min at 908C gave [11C]-1b in 54% RCY (Table 3,
entry 5). An increase of the reaction temperature to 958C
gave a comparable RCY (57%) after only 7 min (Table 3,
Entry
Base/ligand[a]
11CO2 trapped[b] [%]
RCY[c] [%]
1
2
3
4
5
6
7
8
none
pyridine
1,3-imidazole
crypt-222
DMAP
DABCO
PMEDA
DBU
IPr·HCl/tBuOK
(4S,4’S)-PBIPO
(4R,4’R)-PBIPO
DBU+(4S,4’S)-PBIPO
DMEDA
20
24
35
46
51
82
99
97
99
85
83
85
99
97
0
nd[d]
nd
3
nd
19
trace
7
trace
9
9
10
11
12
13
14
7
57
40
49
TMEDA
[a] Abbreviations: DABCO=1,4-diazabicyclo[2.2.2]octane; DMAP=
4-(dimethylamino)pyridine; DMEDA=N,N’-dimethylethylenediamine;
IPr·HCl=1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride; crypt-
222=4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane;
(4S,4’S)-PBIPO=(4S,4’S)-(À)-2,2’-(3-pentylidene)bis(4-isopropyloxazo-
line); (4R,4’R)-PBIPO=(4R,4’R)-(+)-2,2’-(3-isopropylidene)bis(4-
benzyloxazoline); PMEDA=N,N,N’,N’’,N’’-pentamethyldiethylenetria-
mine; TMEDA=N,N,N’,N’-tetramethylethylenediamine. [b] Trapping
efficiency represents decay-corrected trapped radioactivity as percentage
of dispensed radioactivity. [c] RCYs are estimated from dispensed 11CO2.
[d] nd=not determined.
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Table 3: Effects of the fluoride ion source on the RCY of [11C]-1b.[a]
Table 4: Substrate scope of the 11C carboxylation reaction.[a]
Entry
MF
T [8C]
t [min]
RCY [%]
1
2
3
4
5
6
7
CsF
TBAF
KF+18C6
CsF+18C6
KF+crypt-222
KF+crypt-222
KF+crypt-222
KF+crypt-222
KF+crypt-222
90
90
90
90
90
95
100
80
10
10
10
10
10
7
5
5
5
49
trace
38
44
54
57
81
99
99
Substrate
R
Product
RCY [%][b]
1a
2a
3a
4a
5a
6a
7a
8a
phenyl
[11C]-1b
[11C]-2b
[11C]-3b
[11C]-4b
[11C]-5b
[11C]-6b
[11C]-7b
[11C]-8b
[11C]-9b
[11C]-10b
[11C]-11b
[11C]-12b
[11C]-13b
[11C]-14b
[11C]-15b
[11C]-16b
[11C]-17b
[11C]-18b
[11C]-19b
99Æ1
99Æ1
99Æ1
77Æ7
71Æ5
77Æ6
78Æ27
85Æ3
59Æ24
20Æ5
7Æ3
4-methylphenyl
4-formylphenyl
4-bromophenyl
4-chlorophenyl
4-fluorophenyl
4-cyanophenyl
8[b]
9[b]
95
[a] Screening conditions: DMF (400 mL), 1a (50 mmol), TMEDA
(100 mm), CuI (2 mmol), fluoride salt (150 mmol). [b] CuI (0.3 mmol),
KF+crypt-222 (0.9 mmol).
4-nitrophenyl
4-biphenyl
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
4-hydroxyphenyl
2-aminophenyl
3-aminopyrid-5-yl
2-acetamidopyrid-5-yl
4,6-dimethoxypyrimid-2-yl
6-chloropyraz-2-yl
3-methylthien-2-yl
but-1-yl
entry 6). Reaction at 1008C for 5 min gave [11C]-1b in 81%
RCY (Table 3, entry 7). However, the yield decreased at
1108C due to rapid loss of activity from the reaction mixture.
Remarkably, decrease of the CuI catalyst load to 0.3 mmol
and adjustment of the molar ratio of KF+crypt-222 and CuI
to 3:1 gave almost quantitative incorporation of the trapped
11CO2 (Table 3, entries 8 and 9). We attribute this finding to
a stoichiometry effect and reason that a large excess of CuI
shifts the equilibrium towards the organo–copper intermedi-
ate thus hampering reaction with n.c.a. 11CO2. Equally good
results were obtained irrespective of the purity of CuI being
used.
Replacements of DMF with alternative reaction media
were detrimental, except for dimethylacetamide (DMA).
Unlike DMF and DMA, dioxane and 1,2-dimethoxyethane
(DME) were ineffective in combination with TMEDA for
11CO2 trapping. Reactants degraded rapidly in hexamethyl-
phosphoramide (HMPA) or MeCN. Neat TMEDA gave low
yield.
3Æ1
18Æ5
3Æ2
5Æ1
69Æ1
8Æ3
E-2-(4-chlorophenyl)vinyl
5-chlorobut-1-ynyl
91Æ5
70Æ1
[a] Conditions: 11CO2, CuI, TMEDA, crypt-222, KF, DMF, 1008C, 5 min.
[b] RCY values are meanÆ(standard deviation) (n=3).
The most effective conditions (Table 3, entries 8 and 9)
were used to study the substrate scope. A variety of
commercially available boronic acid esters were screened
(Table 4). Many functional groups were found to be compat-
ible with this carboxylation reaction. Sensitive substrates such
as 4-bromo-, 4-cyano- or 4-formylbenzene, which clearly
would not survive exposure to Grignard or organolithium
reagents, gave the desired radioactive products in high to
excellent yields. Even 10a containing a protic hydroxy group
was tolerated to some extent. Amino groups, as in 11a and
12a, were however less tolerated. Electron-deficient hetero-
cycles (13a–15a) generally gave low yields whereas electron-
rich 16a gave a high yield. Unlike alkyl boronic acid ester 17a,
examples of a vinyl (18a) and an alkynyl boronic acid ester
(19a) gave high yields.
Having found that we were able to prepare a variety of
[11C]carboxylic acids efficiently within only 10 min from the
end of radionuclide production, we investigated their further
conversion into labeled derivatives (Scheme 2). Treatment of
crude [11C]-1b with methyl iodide (50 mm) at 1008C for 2 min
gave [11C]benzoic acid methyl ester [11C]-1c in 84% RCY.
The HPLC-purified product was obtained within 18 min from
end of radionuclide production in a radiochemical purity of
> 99% and with a specific radioactivity of 3 CimmolÀ1. No
particular precautions in terms of exclusion of air, a source of
Scheme 2. Rapid conversion of 11C-labeled carboxylic acids into 11C-
labeled esters and amides.
carrier CO2, were necessary to obtain the product with such
high specific radioactivity.
Besides carboxylic acids and esters, carboxamides are
among the most abundant functional groups in biomolecules
and a variety of widely used radiotracers contain benzamide
groups, for example [11C]-(R)-PK11195.[12] We therefore
investigated the conversion of model compound [11C]-1b
into a reactive intermediate for amide formation (Scheme 2)
as follows. Solid-phase extraction of the 11C-labeled acid with
a C18 SPE cartridge was used to remove TMEDA and other
basic constituents from the reaction mixture. The cartridge
was then dried in a stream of helium for 2 min before elution
of [11C]-1b with DMF into a reaction vessel precharged with
SOCl2 (50 mm final concentration). The mixture was heated
to 1008C for 2 min, morpholine (50 mm) was added, and the
mixture was again heated for 2 min. HPLC and LC-MS
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analysis revealed clean conversion of [11C]-1b into amide
[11C]-1d in 46% RCY with a specific radioactivity of
2.5 CimmolÀ1 at 23 min from radionuclide production. We
also investigated the use of carbodiimide reagents for amide
formation. As a proof of principle, diisopropylcarbodiimide
(DIC), DMAP, and N-hydroxysuccinimide (NHS) were used
with [11C]-6b to synthesize [11C]-6d, a 11C-labeled analogue of
the useful peptide- and protein-labeling agent [18F]SFB in
49% RCY.[13]
Experimental Section
11C carboxylation: Cyclotron-produced 11CO2, trapped on a column of
molecular sieves (13X), was released by purging the heated column
(3308C) with He gas at 15 mLminÀ1 and directed into a reaction vial
containing boronic acid ester (60 mmol) and TMEDA (60 mg,
0.5 mmol) plus CuI:crypt-222:KF (0.3:1:1 mmol) in DMF (400 mL).
The reaction vessel was sealed when the radioactivity content reached
a maximum (after about 2 min), heated at 908C for 5 min, and then
rapidly cooled to room temperature. The reaction mixture was
quenched with aqueous formic acid (0.1m, 10 mL) and passed through
a C18 SPE cartridge (Waters). The cartridge was dried in a stream of
He and the [11C]carboxylic acid was eluted in high radiochemical
purity with DMF.
We extended this method to an example of a one-pot
synthesis of a candidate radioligand for PET imaging
(Scheme 3), based on the known oxytocin receptor ligand
Radiosynthesis of [11C]-9d: SOCl2 (25 mmol) in DMF (0.5 mL)
was added to [11C]-9b. This mixture was heated to 1008C for 2 min
before amine 20 (20 mg, 130 mmol) was added. The mixture was then
kept at 508C for 5 min, quenched with water, injected onto
a Luna RP18(2) column (10 mm, 250 mm ꢁ 10 mm, Phenomenex),
and eluted with MeCN/25 mm HCOONH4 (6:4, v/v) at 4.75 mLminÀ1
.
[11C]-9d (tR = 14.5 min) was obtained in 20% RCY.
For details of the other syntheses see the Supporting Information.
Received: October 13, 2011
Revised: January 9, 2012
Published online: February 3, 2012
Keywords: boronic acid esters · carbon-11 · carboxylation ·
.
positron emission tomography · radiochemistry
Scheme 3. Synthesis of the 11C-labeled oxytocin receptor ligand [11C]-
9d.
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9d.[14] Thus, 9a was reacted with 11CO2 as described previ-
ously. Solvent, TMEDA, and unreacted 11CO2 were removed
by evaporation in the vacuum. The residue containing [11C]-
9b was redissolved in DMF, mixed with SOCl2 (50 mm), and
heated to 1008C for 2 min. As no TMEDA was present,
a homogeneous reaction mixture was obtained. Amine 20 was
then added and the mixture kept at 508C for 5 min. HPLC
gave [11C]-9d in 20% RCY at 43 min from radionuclide
production with a radiochemical purity of > 98% and
a specific radioactivity of 1.5 CimmolÀ1. Product identity was
confirmed with HPLC and LC-MS.
We showed herein that CuI-mediated carboxylations of
boronic acid esters are rapid under subatmospheric partial
pressures of 11CO2 in an inert atmosphere in the presence of
a simple combination of TMEDA, KF, and crypt-222. The
resulting [11C]carboxylic acids are obtained in high specific
radioactivity, and they can be rapidly converted into 11C-
labeled esters and amides, thus enhancing the range of
functional groups accessible for labeling. This conversion of
boronates is significantly more tolerant to diverse functional
groups (e.g., halo, nitro or carbonyl) than reactions with
organolithium or organomagnesium reagents. Given the high
prevalence of carboxy groups and their derivatives in PET
radiotracers, paired with the availability of 11CO2 at most PET
centres, we expect this novel method to be widely adapted for
PET radioligand development.
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