Efficient Synthesis of 11C-Acrylesters, 11C-Acrylamides and Their Application in Michael Addition Reactions for PET Tracer Development

Article abstract of DOI:10.1002/ejoc.201700932

Here we present a new Michael addition reaction utilizing carbon-11 labeled acrylic esters and amides. Subsequently, reactions of these synthons with commercially available Schiff base precursors are performed to produce [¹¹C]glutamate and [¹¹C]glutamine. This methodology is especially useful for the development of positron emission tomography (PET) imaging agents as it offers a new array of potential carbon-11 labeled compounds with this original ¹¹C–C bond forming strategy.

Full text of DOI:10.1002/ejoc.201700932

A Journal of
Accepted Article
Title: Efficient synthesis of 11C-acrylesters, 11C-acrylamides and
their application in Michael addition reactions for PET tracer
development.
Authors: Ulrike Filp, Anna Pees, Carlotta Taddei, Aleksandra Pekošak,
Antony D Gee, Albert D Windhorst, and Alex J Poot
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700932
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700932
Supported by

10.1002/ejoc.201700932
European Journal of Organic Chemistry
11
11
Efficient synthesis of C-acrylesters, C-acrylamides and their application in Michael
addition reactions for PET tracer development.
Ulrike Filp1§, Anna L. Pees1, Carlotta Taddei2, Aleksandra Pekošak1, Antony D. Gee2, Albert
D. Windhorst1, Alex J. Poot1
1VU University Medical Center, Department of Radiology and Nuclear Medicine, De Boelelaan
1085c, 1081HV Amsterdam, the Netherlands.
2Division of Imaging Sciences and Biomedical Engineering, King’s College London, Lambeth
Palace Road, SE1 7EH, London, United Kingdom.
§Corresponding author Tel.: +31 20 44 45549; Fax: +31 20 44 49121; E-mail address:
u.filp@vumc.nl (U. Filp)
Abstract
Here we present the novel Michael addition reaction utilizing carbon-11 labeled acrylic esters
and carbon-11 labeled amides. Subsequently, these synthons are reacted with commercially
available Schiff base precursors to produce [11C]glutamate and [11C]glutamine. This
methodology is especially useful for the development of positron emission tomography imaging
agents as it opens up a new array of potential carbon-11 labeled compounds with this original
11C-C bond forming strategy.
Keywords: 11C-acrylester / Michael addition / Pd-catalyzed carbonylation / 11C-labeled amino
acids / Positron Emission Tomography
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Introduction
Positron emission tomography[1] (PET) is an important technique that allows the study
of biological and physiological processes at the molecular level in vivo. To perform PET
imaging the availability of the desired PET tracers, compounds labeled with a positron emitting
nuclide and administered in trace amounts to the study subject, is crucial. New radiochemistry
methodology is needed to enable the development of novel PET imaging agents. Therefore, the
development of synthesis methods for the introduction of positron-emitting radionuclides into
molecules to yield PET agents is important and thus an active area of research. With respect to
frequently used PET radionuclides, carbon-11 (100 % β+, t1/2 = 20.4 min)[2] is one of the most
used for tracer development due to the ubiquity of carbon in all organic molecules. The
challenge in working with carbon-11 is the short half-life and thus fast synthesis procedures are
needed. The total synthesis time, including purification and formulation, should be limited to
approximately 3 half-lives. Currently, most carbon-11 radiolabeling procedures performed are
methylations by alkylation reactions with halogenated carbon-11 labeled reagents, or more
activated [11C]methyl triflate, further carboxylation reactions from [11C]CO2 or palladium-
catalyzed [11C]CO insertion reactions.[3–5] Other carbon-11 labeling reactions are known, but
hardly applied for PET tracer development.[6]
In this paper we describe the potential of Michael addition reactions where the Michael
acceptor is labeled with carbon-11. This reaction has been proposed by Antoni et al., however
its potential in radiosynthesis has not been further demonstrated.[7] To this end, we have
synthesized functionalized 11C-acrylesters and 11C-acrylamides as versatile radiolabeling
reagents and investigated their subsequent use as Michael acceptors, a novel radiochemical
methodology to form 11C-C bonds and potentially novel PET imaging agents. Moreover, by the
formation of a 11C-C bond, this reaction has the potential to form novel chiral centers, which is
a unique challenge for radiochemistry development. As proof-of-concept, the focus was laid on
the radiosyntheses of the amino acids (AAs) [11C]glutamate and [11C]glutamine by making use
of the Michael addition with the corresponding 11C-acrylester and an activated glycine Schiff
base precursor.
To synthesize the desired 11C-labeled synthons for the Michael additions, two methods
11
have been investigated. The first approach to develop C-acrylesters made use of Grignard
reactions between different vinyl magnesium halides and [11C]CO2,followed by quenching with
a nucleophile to obtain the Michael acceptor acrylic acid 1[8] or the methyl acrylate 2 for further
synthesis. Carbon-11 labeled acrylic acid and its methyl ester, 1 and 2, have been reported
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
before, however only in low molar activity1 (AM). Furthermore, the application of these
reagents was limited to 1,2-additions. The second approach implemented here is a Pd-mediated
carbonylation reaction with [11C]CO to obtain acrylester 3 and acrylamide 4.[9,10] Another
advantage, when applying the second methodology is the low isotopic dilution when making
use of [11C]CO compared to [11C]CO2, which in general yields higher AM. The more widespread
application of [11C]CO became available in 2013 when Eriksson et al. published a simplified
procedure for the transfer of [11C]CO making use of xenon gas as well as Dahl et al. introducing
xanthpos as trapping support agent, which caused a major breakthrough.[10,11] Moreover,
nowadays also alternative procedures have been published to obtain [11C]CO from [11C]CO2
using simplified and straightforward methodologies.[5,12–14]
Scheme 1. Online transformations possible in carbon-11 chemistry: i) Reduction with
molybdenum at 850 °C; ii) Coupling of [11C]CO2 with Vinyl-MgBr and quenching with water;
iii) Coupling of [11C]CO2 with Vinyl-MgBr, after addition of sulfuric acid and methanol; iv)
Coupling of [11C]CO with Vinyl-I and Pd-xantphos with tert-butanol; v) Coupling of [11C]CO
with Vinyl-I and Pd-xantphos with tritylamine, vi) Michael addition with base.
As exemplified in Scheme 1, for the Michael addition with 11C-acrylesters, the reactivity
and thus the versatility of these reagents was investigated by reaction with Schiff base glycine
derivatives (5) as Michael donor. A functional AA is created being [11C]glutamate,
[11C]glutamine or derivatives thereof by exploiting this Michael addition to the Schiff base.
Michael addition reactions are also known as 1,4-additions, where the C-C bond-forming ability
is employed traditionally by an enolate that reacts with an α,β-unsaturated carbonyl compound
(Scheme 2). An additional challenge for the Michael reactions explored in this paper is that the
AAs formed are chiral molecules. For this reason the chiral induction during the Michael
1 Molar activity: measured radioactivity per mole of compound (GBq∙μmol-1) readjusted from specific activiy.
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
addition is explored by using phase-transfer catalysis (PTC). The asymmetric radiolabeling
approach with highly specialized chiral catalysts is unique and highly valuable to radiolabel
chiral compounds. To date, this methodology has been successfully described in radiosynthesis
of [11C]alanine[15] and [11C]phenylalanine[16], as well as for dipeptides (EurJOC, submitted) and
12
tetrapeptides[17]. In addition, the asymmetric Michael addition[18,19] has been explored in C-
organic chemistry, however this challenging radiosynthesis method is unprecedented in
radiochemistry thus far.
In this paper we will describe the syntheses, optimization and application of 11C-acrylesters and
11C-acrylamides 1 – 4 as reagents to be applied in Michael addition reactions for the
development of PET imaging agents as exemplified by products 6 – 11.
Scheme 2. Proposed mechanism of a racemic alkylation of a Schiff base for AA synthesis.
Results & Discussion
Radiosynthesis of 11C-acrylesters using a Grignard reaction
First focus was to obtain 11C-acrylesters by performing a Grignard reaction between vinyl
magnesium bromide, which is reacted with cyclotron produced [11C]CO2 followed by
quenching with a nucleophile to obtain [11C]acrylic acid or [11C]methyl acrylate.[8,20] The
optimization led to quantitative trapping of [11C]CO2 from the transfer lines in a solution of
vinyl magnesium bromide as reagent in THF at low temperatures. A reaction was achieved by
increasing the temperature to room temperature (rt) over a period of 2 min with a constant He-
flow of 10 mL∙min-1. The reaction mixture was quenched with 2M HCl and this resulted in the
radiosynthesis of [11C]1 as reagent to be used in Michael addition reactions. The radiochemical
conversion to product in the crude reaction mixture, determined by analytical HPLC and
defined as radiochemical purity (RCP) to compound [11C]1 was satisfying 50-70 %.
In addition to the radiosynthesis of [11C]1, the reaction conditions have been modified as such
that acrylic esters could be formed as well. Therefore, the magnesium acrylic acid formed in
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
the Grignard reaction between vinyl magnesium bromide and [11C]CO2, was quenched with
methanol and sulfuric acid and allowed the esterification of the product to obtain [11C]2 with a
RCP between 65-78 % determined by analytical HPLC. Purification from the crude reaction
mixture was achieved by distillation at 90 ºC into a cooled second reaction vial yielding highly
purified [11C]2. The average isolated radiochemical decay corrected (d.c.) yield obtained for
this two-step reaction was 21-23 %, resulting in 0.43-0.47 GBq of product after 15 min
synthesis time starting from 2.0 GBq [11C]CO2 (N=5).
Radiosynthesis to obtain [11C]tert-butylacrylate and [11C]N-tritylacrylamide
To investigate the radiosynthesis of other functionalized 11C-acrylesters and to be able to obtain
11C-acrylamides, the focus shifted to Pd-catalyzed carbonylation reactions with [11C]CO. To be
able to perform these reactions, first the reduction from [11C]CO2 to [11C]CO was performed
according to the procedures described by Eriksson et al. and Van der Wildt et al.[11,21] Here
[11C]CO2 was reduced to [11C]CO by passing it online through a molybdenum filled column
heated to 850 °C. The product was collected on a silica trap that was cooled in liquid N2.
Unreacted [11C]CO2 was removed by trapping it on an ascarite trap. For optimal transfer of
[11C]CO to the reaction vial, the silica trap was heated to release the [11C]CO and with a gentle
flow of xenon (3.0 mL∙min-1) the [11C]CO was efficiently transferred to the previously charged
and sealed reagent vial for carbonylation. Making use of the Pd-catalyzed carbonylation
reactions with [11C]CO, the radiosyntheses of [11C]tert-butylacrylate 3 and [11C]trityl-
acrylamide 4 were investigated.[9]
As summarized in Table 1, initially the synthesis of acrylester [11C]3 and acrylamide [11C]4
were examined making use of Pd2(dba)3 as a catalyst in the presence of PPh3 as supporting
ligand. However, only low conversions were observed using this strategy (Table 1: Entry 1-3,
6). The trapping efficacy of [11C]CO in THF supported with xantphos was more successful.[10]
The optimal radiochemical conversion obtained to synthesize acrylester [11C]3 and acrylamide
[11C]4 were established using [(Cinnamyl)PdCl]2 as a catalyst[22] (Table 1: Entry 4-5, 9) and the
RCP for either synthon was >75 % and amounted to isolated radiochemical yield of [11C]3 to
0.41-0.45 GBq (18-20 % d.c. yield, 25 min, N=2) and 0.42-0.44 GBq of [11C]4 (22-23 % d.c.
yield, 25 min, N=3) from 2.5 GBq of [11C]CO2.
Table 1. RCPs for the synthesis of [11C]3 and [11C]4 with [11C]CO.
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Vinyl halide
Ligand
(µmol)
[a]
#
Product
Pd-source (µmol)
[Pd2(dba)3] (2.4)
[Pd2(dba)3] (10)
[Pd2(dba)3] (1.2)
RCP ± SD (%)
(µmol)
Vinyl bromide
(20)
45.0 ± 5.1
(N=2)
1[b]
PPh3 (20)
PPh3 (20)
Vinyl bromide
(65)
11.2
2.0
2
[11C]3
Vinyl bromide
(10)
PPh3 (10)
3
[(Cinnamyl)PdCl]2
(7)
80.2 ± 5.2
(N=2)
AsPh3 (56)
Xanthpos (7)
PPh3 (20)
4
Vinyl iodide (10)
[(Cinnamyl)PdCl]2
(7)
79.0 ± 10.0
(N=15)
5
Vinyl bromide
(20)
14.3 ± 2.1
(N=2)
6[c]
Pd2(dba)3 (2.4)
[(Cinnamyl)PdCl]2
(7)
75.1 ± 1.2
(N=2)
7[d]
8[c]
9[d]
AsPh3 (56)
[11C]4
Vinyl iodide (10)
9.0 ± 6.2 (N=2)
[(Cinnamyl)PdCl]2
(7)
Xanthpos (7)
73.0 ± 5.0
(N=10)
[a]Reaction performed in THF 450 µL for 3-5 min at 100 ºC; [b]t-BuOH: Entry 1-3 2600 μmol;
4-5: 2100 μmol; [c]Tritylamine 20 μmol; [d]Tritylamine 96 μmol.
Successful [11C]CO insertion reactions are dependent on the use of high concentrations of the
nucleophile, tert-butanol (t-BuOH) for the radiosynthesis of [11C]3 and tritylamine for [11C]4.
The high amount of t-BuOH used is due to its technical handling losses, and its ability as
solvent. For the radiosynthesis of acryl amides, solid tritylamine was used. Since this cannot be
added in such great excess, lower quantities (Table 1: Entry 6; 8) were used but proved to be
low yielding, therefore minimal amount of 96 μmol was found to be required in the reaction.
The AM of product [11C]4 determined after preparative purification was high and ranged from
86-170 GBq∙μmol-1 starting with an activity of approximately 2.5 GBq of [11C]CO2. Also [11C]3
was isolated on preparative scale with a minimum calculated AM of 53.4 GBq·µmol-1; however,
due to the low UV absorbance of [11C]3 no AM with acceptable precision could be determined
experimentally.
11C-acrylates, however proved to be unstable, which was investigated by radioHPLC
while mimicking the reaction conditions of the Michael addition in the presence of high
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
amounts of base like CsOH∙H2O.[15,23] The radiosynthesis of synthons [11C]3 and [11C]4 was
performed according to the optimized procedure and subsequently the synthons were added to
various amounts of CsOH∙H2O (2.0-8.9 M) in toluene. The samples were left for 5 min at rt and
at 100 ºC before the analysis, results are listed in Table 2.
Table 2. Stability of [11C]3 and [11C]4 with CsOH·H2O at rt and 100 ºC.
[11C]3
(% intact) (% intact)
[11C]4
CsOH∙H2O
[a]
#
T (ºC)
(M)
2.0
71.6 ± 4.5 82.0 ± 2.0
1
2
3
4
5
20
8.9
31.0 ± 3.2 79.5 ± 6.5
79.0 ± 10.0 73.0 ± 5.0
/
2.0 or 8.9
/
0
43.0
100
76.2 ± 3.0 72.5 ± 3.0
[a]Reaction performed in 100 μL of toluene; N=2.
The major decomposition product of [11C]3 is [11C]acrylic acid, which was confirmed by HPLC
(see Supporting Information). If the solution was heated to 100 ºC for 5 min no [11C]3 could be
detected at the end of the reaction. In contrast, [11C]4 showed minimal decomposition at rt, also
in the presence of high amounts of CsOH·H2O. The stability, even at higher temperatures, is
better compared to [11C]3 and still 43 % were intact after 5 min. This can be explained by the
resonance stability of the amide which is stronger compared to esters. Notwithstanding these
limitations, with the carbon-11 labeled acrylates 1 – 4 in hand the potential of these reagents
was explored in Michael addition reactions.
Michael addition reaction
Initially, the Michael reactions (Scheme 3) were performed without intermediate
purification of the carbon-11 labeled acrylic derivatives; however, no conversion to Michael
adducts was observed. Since it was expected that the impurities in the crude reaction mixture
obstructed successful Michael additions, various purifications of the 11C-acrylates were
explored. Purification of [11C]2 was simply achieved by distillation. Unfortunately, this
approach was not successful for [11C]1, [11C]3 and [11C]4. Solid-phase purification of the latter
compounds were evaluated utilizing C18 and Alumina N SepPaks with a PTFE-filter, but were
unsuccessful. Finally, passing the reaction mixture over custom made cartridge loaded with
approximately 200 mg of Celite afforded [11C]3 and [11C]4 in sufficient purity to allow its use
in Michael reactions.
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Racemic Michael addition with synthons [11C]1 and [11C]2
After optimizing the radiosynthesis procedures to obtain the 11C-acrylesters, [11C]1 was
used as a Michael acceptor with the Schiff base precursor 5 as donor. Whereas acidic conditions
were used for the hydrolysis of the magnesium-acrylester salts to obtain [11C]1, an initial
challenge was changing to basic conditions, which are needed for the second reaction, the C-C
bond forming to the glycine moiety. In acidic reaction conditions, the Schiff base enolate cannot
be formed and the reaction of the donor to the acceptor will not proceed. Likewise, no reaction
occurred in highly basic conditions leaving unreacted 5, which is likely to be caused by the low
acceptor ability of [11C]1.
However, utilizing distilled [11C]2, the Michael addition reaction yielding [11C]7 was
successful, as described in Scheme 3. For evaluation of the reactivity of [11C]2, reactions were
successfully performed with 5 in DMSO and TBAF (tetrabutyl ammonium fluoride) as base,
reaction conditions that have also been used by Kato et al.[24] to alkylate 5. The reaction was
successful with overall conversion yields of up to 90 % determined by analytical radioHPLC.
In addition to TBAF as an organic base, inorganic alkali-metal bases were explored to
deprotonate 5 and perform the Michael additions. Alkali-metal bases were selected due to their
widespread application in asymmetric syntheses.[23] However, hydrolysis of [11C]2 was mainly
observed with CsOH·H2O or KOH. Evidently, this competing reaction turned out to be faster
than the Michael addition reaction, resulting in a drop in yields. Nonetheless, 10-15 % RCP of
[11C]10 were obtained, assessed by chiral radioHPLC after the acidic deprotection of the imine
and tert-butylester.
Scheme 3. Michael addition reaction with synthon 1 - 4 to obtain Michael addition products.
These results further support the suitability of Michael addition reactions in the
development of PET imaging agents for advanced carbon-11 labeled synthesis. The
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
applicability of this reaction has certain limitations. For instance, the reaction to obtain [11C]6
did not occur and the reaction to obtain [11C]7 was only possible with TBAF as a base. In order
to overcome these issues, the research was further focused on the synthesis of [11C]8 and [11C]9,
utilizing [11C]3 and [11C]4 that are evidently more stable under previously described reaction
conditions.
Racemic Michael addition with synthons [11C]3 and [11C]4
The concentration of precursor 5, reaction time, type and amount of base and reaction
temperature were initially optimized for [11C]8 and [11C]9 in order to obtain high 11C-C addition
yields. The effect of the precursor concentration was also investigated, using TBAF as a base.
An increased amount of Schiff base 5 ranging between 170-330 mM was necessary to obtain
higher RCPs. These high concentrations are attributed to the decomposition of 5 to
benzophenone and glycine tert-butylester. Alkylation of 5 with [11C]3 according to procedures
earlier described[24,25] was successful and yielded RCPs of 93.2 ± 5.7 % (N=5) and 78.1 ± 3.0
% (N=3) for [11C]8 and [11C]9 with TBAF (0.33 mM) in DMSO at 100 ºC for 5 min,
respectively.
Solid inorganic bases for Michael reaction
As stated previously, alkali-metal bases are preferred in chiral PTC reactions,
consequently various inorganic alkali-metal bases (Table 3), which are described in literature
have been screened for their alkylation potential in toluene at 10 ºC, thus far optimal conditions
for chiral reactions.[15] Generally, lower temperatures are favored in PTC reactions to enhance
stereoselecitivity, therefore we focused with inorganic bases on lower temperatures. Due to a
solid-liquid phase reaction taking place, a sufficient interfacial area between the two phases
needs to be created by vigorous stirring.
Table 3. Michael alkylation reactions with different bases to obtain [11C]9.
[a]
#
Base
KOH
Equiv.[b] RCP ± SD (%)
N
4
4
4
2
4
2
5.9
10.5
< 2
< 2
1
KOH
2
3
4
5
6
P1-tBu
RbOH
RbOH
5.0
< 1
9.8
< 2
14.0-19.0
< 5
RbOH[c] 14.0-19.0
21.1 ± 5.8
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
CsOH∙H2O
10.5
51.2 ± 30.0
9
7
[a]Reaction performed with 170 mM 5 in toluene at 10 ºC for 5 min; [b]Compared to 5;
[c]Reaction performed at 50 ºC.
From these experiments it was concluded that CsOH∙H2O as base in the reaction is
superior over other alkali-metal bases investigated. Furthermore, the relative small variation in
equivalents – also due to strong hygroscopicity of inorganic bases used, did not influence the
outcome of the reaction to product (Table 3: Entry 1-2, 4-5). Remarkably, rather modest
conversions were observed, in contrast to previously reported results in organic
chemistry.[18,26,27] This is presumably caused by the reaction time, since in carbon-11
radiosynthesis only rapid reactions can be considered due to the half-life of 20 min, whereas in
organic chemistry longer reaction times are feasible.
Kinetic analysis to obtain [11C]9
To establish an improved procedure for the production of [11C]9, a kinetic analysis was
performed. Samples were taken from the start of reaction until 5 min, which was confirmed as
optimal reaction time (Figure 1 A).
Figure 1. A) Kinetic analysis of the formation of [11C]9 as function of reaction time, assessed
with HPLC; B) Exemplified radiochromatogram of the crude reaction mixture after 5 min.
By utilizing radio-TLC over HPLC we have monitored the entire reaction to overcome the
breakdown of aqueous sensitive intermediates, thereby confirming the stability and availability
of the Schiff base (see Supporting Information: Stability of 5). We observed precursor 5
consistently during the reaction, however also the presence of the decomposition product
benzophenone was detectable. Despite of the decomposition, seemingly there was enough
precursor 5 available for the Michael addition and benzophenone did not disturb this reaction.
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
It was important to bear in mind to add precursor 5 as late as possible to the reaction mixture
for the Michael addition. Furthermore, between 50-100 nmol (low μM) of labeling reagent is
typically used, resulting in large excess of non-radiolabeled reagents which are typically in the
μmol (mM) range. These non-stoichiometric reaction conditions can result in the operation of
pseudo-first order kinetics with respect to the non-labeled reagents employed. In spite of the
fact that the amount of 11C-labeled reagent is fairly stable, the synthons were steadily
decomposing as well, resulting in variations in RCP. However, once product [11C]8 or [11C]9
were formed, they were stable.
So far a 10-fold excess of base (CsOH∙H2O) to Schiff base precursor 5 was used in this
type of reactions[15] and since [11C]4 is more stable with higher quantities of base, the Michael
addition reactions were investigated with elevated base concentrations, see Table 4. Increasing
the amount of base resulted in significantly lower yields which most probably is caused by
decomposition of [11C]4. Regarding the synthesis of [11C]8, stability experiments already
showed that higher amounts of base led to partial decomposition of reagent [11C]3, so further
experiments were abandoned. To conclude, 10.5 equivalents of base relative to 5 gave the best
results.
Table 4. Radiosynthesis of [11C]9 with varying amounts of CsOH∙H2O.
[a]
#
CsOH·H2O equiv.[b] RCP (%)
N
10.5
15.3
20.9
105
51.2 ± 30.0 9
34.4 ± 13.2 2
30.6 ± 12.7 2
1
2
3
4
33.8 ± 6.1
4
[a]Reaction performed with 170 mM of 5 in toluene at 10 ºC for 5 min; [b]Compared to 5.
Reactions of most suitable synthons with phase-transfer catalysts
Figure 2. Chiral PTCs explored in PTC reactions for Michael additions: quaternary ammonium
salt 12 and 13; tartare-derived catalyst 14 and 15; Brønsted base 16.
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
In order to induce an enantioselective Michael addition reaction, the application of chiral PTCs
was investigated as described in literature in organic chemistry.[18,23,28] With regard to the
constraints presented in radiochemistry like time as limiting factor, as well as the non-catalytic
reaction conditions in which the chiral catalysts are used in stoichiometric amounts compared
to the precursor material and in excess of the 11C-labeled reagent, the translation of PTC
reaction conditions to radiochemistry has been challenging.[15–17]
Scheme 4. Asymmetric Synthesis of Michael addition products.
In Table 5, results are summarized of asymmetric synthesis with the various catalysts
that were commercially available.[15,16]
Table 5. RCP (in % ± SD, N ≥ 2) of alkylation with synthons to obtain [11C]8 and [11C]9.
[a]
#
Product Temp (°C)
Cat 12
Cat 13
Cat 14
Cat 15
Cat 16
20
31.1 ± 29.1
n.d.
23.2 ± 16.5
1
1
[11C]8
n.d.[b]
10
32.1 ± 21.1 28.8 ± 0.4 44.1 ± 21.4 42.6 ± 6.7
2
3
4
5
20
31.0± 7.2
18.4
5.4 ± 2.8 37.6 ± 25.3
16.5 ± 4.4 5.3 ± 2.9
2
n.d.
0
[11C]9
15
10
n.d.
16.3 ± 13.3 33.8 ± 6.1 15.5 ± 13.4
[a]Reaction performed with 170 mM of 5; 10.5 equiv. of CsOH∙H2O in toluene with 0.1 mol%
of Cat at 10 ºC for 5 min with vigorous stirring; [b]n.d. not determined.
With RCPs not exceeding 50 % all reactions resulted in moderate conversions for both [11C]8
and [11C]9 (Table 5), however with lower temperature the conversions were slightly higher.
Tartrate-derived catalysts 14 and 15 resulted in good enantiomeric ratios in Michael addition
reactions in organic chemistry[19,29-30] and this was also observed under radiochemistry
conditions. Catalysts 12 and 13 gave unsatisfactory results, hardly any enantiomeric enrichment
was observed in contrary to results obtained for previous studies to obtain L-[11C]alanine.[15]
Furthermore, during the conduct of the study Bander et al. introduced the concept of using a
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
chiral Brønsted base 16 capable of catalyzing proton transfer reactions enantioselectively.[31]
Unfortunately, it was not possible to reproduce these results under radiochemistry conditions.
Ultimately, the difference in the asymmetric radiochemistry reactions presented so far in
literature, is the formation of a new C-C bond, which is an alkylation reaction with a reactive
alkylating agent and in the latter an 1,4-addition with constraints concerning availability of 11C-
reagent and stability issues.
The enantiomeric ratio obtained with catalyst 14 (Figure 3) is presented in Table 6.
These were determined with chiral HPLC of the resulting AAs after complete deprotection with
0.1 mL of 6M HCl and heating to 100 ºC for 2 min.
Figure 3. Analysis of L-and D-[11C]10 with chiral radioHPLC.
Table 6. Enantiomeric ratio (in %, ± SD, N ≥ 2) of L-and D-[11C]10 with Cat 14.
[a]
#
Equiv. of 14 L-[11C]Glu D-[11C]Glu
/
51 ± 3
49 ± 3
1
0.1
0.5
60 ± 5
61 ± 4
40 ± 5
39 ± 4
2
3
[a]Reactions performed with 170 mM of 5 in 100 μL of toluene with 12-14 equiv. CsOH·H2O
at 10 ºC for 5 min.
The enantiomeric ratios are lower compared to traditional 12C-organic chemistry
procedures, where longer reaction times are possible, furthermore lower temperatures are
applied to obtain excellent enatiomeric ratios. From Table 6 it can be concluded that the catalyst
positively influenced the ratio towards the desired enantiomer, compared to no catalyst in the
reaction mixture (Table 6: Entry 1). Nevertheless, it was not possible to obtain satisfactory
enantiomeric ratios for the synthesis of [11C]10. Therefore, studies to obtain enantomerically
enriched [11C]11 with synthon [11C]4 were not explored. Unarguably, the asymmetric syntheses
13
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
with presented catalysts have not been as successful and we believe the distorted conditions led
to the catalyst-enolate complex not forming properly. Regardless, a new methodology for the
formation of a covalent 11C-C bond has been explored and presents new strategies for AA
synthesis.
Furthermore, a reason for the variation in RCP might be the Pd-ligand complex, utilized
in the [11C]CO insertion reaction, which cannot be completely removed from the reaction via
the celite purification. As a control experiment, we have synthesized [11C]alanine[15] and added
the same Pd-ligand complex to the phase-transfer catalyst alkylation reaction in approximately
the same amount. The addition of the Pd-complex caused a complete depletion of yield
compared to the original conditions, thereby proving the negative influence of the Pd-complex
on the alkylation reaction (details in Supporting Information). Presumably the phase-transfer
catalyst and the Pd-complex are not compatible and hindering the reaction by either not
activating 5 to form the enolate or/and cause de-activation of catalyst.
Conclusion
Here we have demonstrated for the first time the feasibility of Michael addition reactions
in radiochemistry, where the Michael acceptor was labeled with carbon-11 after reaction with
an acrylate. The Michael addition creates new possibilities for the synthesis of carbon-11
labeled PET tracer candidates. Further research is ongoing for the enantioselective Michael
addition radiosynthesis.
Acknowledgements
This study received funding from the European Union, Marie Curie actions RADIOMI (FP7-
PEOPLE-2012-ITN) under project reference no. 316882. We gratefully acknowledge the BV
Cyclotron VU for providing [11C]CO2.
14
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Material & Methods
General
All chemicals were purchased from commercial sources (Sigma Aldrich (Zwijndrecht, The
Netherlands), Bachem (Bubendorf, Switzerland), ABCR (Karlsruhe, Germany), Santa Cruz
Biotechnology (Bio-Connect B.V., Huissen, the Netherlands)) and used without further
purification. Solvents were purchased from Biosolve (Valkenswaard, the Netherlands) and used
as received unless stated otherwise. Reactions were monitored by thin layer chromatography
on pre-coated silica 60 F254 aluminum plates (Merck, Darmstadt, Germany). Spots on TLC
were visualized by UV light and staining with ninhydrine and potassium permanganate
solutions. Solvents were evaporated under reduced pressure using a rotary evaporator
(Rotavapor® R II, Flawil, Switzerland). Flash chromatography purifications were performed
on a Buchi operated by SepacoreControl system. Non-radioactive reference compounds were
synthesized according to reported methods and were used to verify the identity of the
radiolabeled products.
1H and 13C Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker AC
500.23, 400.13 or 250.13 MHz (Billerica, USA) and chemical shifts (δ) were defined relative
to the signal of the solvent (7.27 ppm for CDCl3, 3.31 ppm for MeOH-d4 , 2.50 ppm for DMSO-
d6). High resolution mass spectra (HRMS) were carried out using a Bruker microTOF-Q
instrument in positive or negative ion mode (capillary potential of 4500 V). Analytical HPLC
systems used were equipped with: a Waters 600E pump, a manual Rheodyne injector (20-100
µL loop), a Waters PDA and GinaStar software from Raytest (Germany). The radioactive
profile was monitored with a Raytest 2.5 inch radioactivity detector (Raytest, Germany). Small
synthons [11C]1 - 4 were analyzed with a Grace Smart C18 HPLC column obtained from Grace
Alltech (4.6 x 250 mm, 5 μm) with acetonitrile/sodiumformate 4 mM + 4 % DMF (buffer 1)
(68/32, v/v) as eluent unless stated otherwise. Michael adducts [11C]6 - 9 were measured on a
Great Smart (4.6 x 250 mm, 5 μm; formerly known as Grace Smart, Dr. Maisch, Ammerbuch,
Germany) with acetonitrile/buffer 1 (65/35, v/v) or as stated otherwise, UV monitoring at 254
nm. Flow rates for all HPLC analysis were 1 mL∙min-1 unless stated otherwise. HPLC
preparative purification of synthons [11C]3 and [11C]4 was performed on Alltima C18 (22 x 250
mm, 10 μm) with acetonitrile/buffer 1 70/30 (v/v) with a flow of 4 mL·min-1. Enantiomeric
purity of the products [11C]10 – 11 was determined using an analytical Reprosil chiral-AA (4.6
x 250 mm) from Dr. Maisch GmbH at 214 nm. The product was eluted with methanol/water
(70/30 or 90/10, v/v).
15
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Radiochemical conversion was determined by HPLC analysis as the percentage of converted
carbon-11 labeled reagent to the desired product in the crude reaction mixture, which is based
on the AUC of the radioactivity profile, using analytical HPLC and expressed here as
Radiochemical purity (RCP). Radiochemical yield (RCY) is the amount of radioactivity in the
product expressed as the percentage of related starting radioactivity used in the corresponding
synthesis. RCY was calculated as the quotient of measured activity of the isolated product at
the end of synthesis (EOS) and the measured activity at the end of the cyclotron bombardment
(EOB) in the vessel at the beginning of the synthesis, both measured in a dose calibrator, and
expressed as a percentage. Radiochemical yield has been corrected for decay from EOB, no
other corrections for radioactivity losses have been made.
Molar activity (AM) of the radioactive intermediates (e.g. [11C]4) after preparative HPLC
purification was determined by measurement of the UV absorbance of a known amount of
radioactivity under identical analytical HPLC conditions used to generate a molar calibration
curve for the corresponding non-radioactive standard.
16
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Synthesis of reference compounds
Tritylacrylamide 4[32]
Acrylamide (500 mg, 7.030 mmol), triphenylmethanol (964 mg, 3.700 mmol) and para-
toluenesulfonic acid monohydrate (444 mg, 2.330 mmol) were refluxed in 100 mL of toluene.
After 4 hours, the solution was cooled to room temperature and quenched with 50 mL of 2 %
aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 x
50 mL) and the combined organic extracts were washed with water and brine. After drying over
sodium sulfate (Na2SO4) and evaporating the solvent, the product was purified on a silica
column (hexane/ethyl acetate, first 5:1 then 1:1) affording 935 mg (2.980 mmol, 81 %) of
colorless crystals.
1H-NMR (500.13 MHz, CDCl3): δ = 7.34-7.23 (m, 15H, 3x –Ph), 6.27 (dd, 2H, J=5.0, 2.5 Hz,
=CH2), 5.67 (dd, 1H, J=5.0, 2.5 Hz, –CH) ppm; 13C-NMR (125.62 MHz, CDCl3): δ = 164.45,
144.55, 131.43, 128.72, 128.03, 127.13, 70.66 ppm; HRMS (ESI) calculated for C22H19NO:
314.1545 [(M+H)]+, found: 314.1520 [(M+H)]+, 336.1343 [(M+Na)]+.
Tert-butyl 2-((diphenylmethylene)amino)-5-oxo-5-(tritylamino)pentanoate
N-(Diphenylmethylene)glycine tert-butylester (100 mg, 0.340 mmol) and N-tritylacrylamide
(300 mg, 0.960 mmol) were dissolved in 3 mL of dimethylsulfoxide (DMSO). Additionally,
1 mL of 1 M solution of TBAF in tetrahydrofuran (THF) was added and the dark red solution
was stirred for two hours at room temperature. After being diluted with 60 mL of diethyl ether,
the organic phase was washed with H2O (2 x 20 mL), brine (40 mL), dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude product was purified by silica
chromatography twice (1) 5-16 % ethyl acetate/hexane, (2) 0-15 % MeOH/DCM in 20 min,
which afforded 48.0 mg of a light yellow solid (0.080 mmol, 23 %).
17
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
1H-NMR (400.13 MHz, CDCl3): δ = 7.67 (d, 2H, J=8.0 Hz, –Ph), 7.35-7.23 (m, 15H, 3x –Ph),
7.20-7.16 (m, 8H, 2x –Ph), 4.03 (t, 1H, J=8.0 Hz, –CH), 2.40-2.36 (m, 2H, –CH2), 2.29-2.25
13
(m, 2H, –CH2), 1.44 (s, 9H, 3x –CH3) ppm; C-NMR (100.62 MHz, CDCl3): δ = 171.36,
170.87, 144.77, 139.50, 136.44, 132.40, 130.33, 128.78, 128.69, 127.90, 126.94, 81.24, 65.06,
34.20, 29.58, 28.05 ppm; HRMS (ESI) calculated for C41H40N2O3 609.3117 [(M+H)]+, found:
609.3046 [(M+H)]+.
(S)-Di-tert-butyl 2-((diphenylmethylene)amino)pentanedioate
N-(Diphenylmethylene)glycine tert-butylester (200 mg, 0.680 mmol) and the phase transfer
catalyst 12 (40 mg, 0.030 mmol) were dissolved in 2 mL DCM and 0.4 mL of 50 % (w/w)
potassium hydroxide solution was added. Tert-butyl acrylate (87 mg, 0.677 mmol) was added
dropwise and the reaction mixture was stirred overnight at room temperature. After dilution
with 120 mL of ethyl acetate the organic phase was washed with H2O (2 x 40 mL), brine (80
mL), dried over Na2SO4 and concentrated in vacuo. By purification of the residue by silica
chromatography (20:1 to 5:1 hexane/ethyl acetate) 196 mg (0.463 mmol, 68 %) of a colorless
oil could be obtained.
1H-NMR (250.13 MHz, CDCl3): δ = 7.68-7.66 (m, 2H, –Ph), 7.45-7.33 (m, 6H, –Ph), 7.21-7.18
(m, 2H, –Ph), 3.98 (t, 1H, J=2.5 Hz, –CH), 2.27-2.21 (m, 4H, 2x –CH2), 1.46 (s, 9H, 3x –CH3),
1.41 (s, 9H, 3x –CH3) ppm; 13C-NMR (100.62 MHz, CDCl3): δ = 170.90, 170.59, 139.55,
132.42, 130.06, 128.81, 127.99, 127.81, 80.17, 64.98, 32.01, 28.89, 28.07 ppm; HRMS (ESI)
calculated for C26H33NO4: 424.2488 [(M+H)]+, found: 424.2388 [(M+H)]+, 446.2208
[(M+Na)]+.
(R)-Di-tert-butyl 2-((diphenylmethylene)amino)pentanedioate
18
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
(R)-Di-tert-butyl 2-aminopentanedioate (200 mg, 0.770 mmol) was stirred overnight at rt with
benzophenone imine (129 μL, 0.770 mmol) in DCM (5 mL). The solvent was evaporated and
the mixture purified by flash chromatography (20:1 to 5:1 hexane/ethyl acetate) resulting in 308
mg of a colorless oil (0.730 mmol, 94 %).
1H-NMR (250.13 MHz, CDCl3): δ = 7.70-7.64 (m, 2H, –Ph), 7.46-7.38 (m, 6H, –Ph), 7.22-7.18
(m, 2H, –Ph), 4.00 (t, 1H, J=5.0 Hz, –CH), 2.31-2.21 (m, 4H, 2x – CH2), 1.46 (s, 9H, 3x –CH3),
1.41 (s, 9H, 3x –CH3) ppm; 13C-NMR (100.62 MHz, CDCl3): δ = 172.47, 170.88, 139.58,
136.55, 130.24, 128.80, 127.98, 127.81, 80.06, 64.99, 32.01, 32.01, 28.91, 28.07 ppm; HRMS
(ESI) calculated for C26H33NO4: 424.2488 [(M+H)]+, found: 424.2482 [(M+H)]+.
1-(Tert-butyl)5-methyl 2-((diphenylmethylene)amino)pentanedioate
N-(Diphenylmethylene)glycine tert-butylester (100 mg, 0.340 mmol) and the catalyst 12 (20
mg, 0.030 mmol) were dissolved in 1 mL of DCM, then 0.2 mL of 50 % (w/w) aqueous
potassium hydroxide solution was added dropwise and the mixture was cooled to -50 °C. A
solution of methyl acrylate (0.1 mL, 1.097 mmol) in 0.2 mL DCM was added dropwise and
stirred for 4 hours at -50 °C. After being diluted with 60 mL of diethyl ether, the organic phase
was washed with H2O (2 x 20 mL), brine (40 mL), dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by silica chromatography (hexane/ethyl acetate 20:1 to
5:1), which afforded the product as colorless oil (87.0 mg, 67 %).
1H-NMR (250.13 MHz, CDCl3): δ = 7.55-7.60 (m, 2H, –Ph), 7.21-7.40 (m, 6H, –Ph), 7.07-7.15
(m, 2H, –Ph), 3.90 (t, 1H, J=6.3 Hz, –CH), 3.52 (s, 3H, –OCH3), 2.25-2.35 (m, 2H, –CH2),
13
2.09-2.20 (m, 2H, –CH2), 1.37 (s, 9H, 3x –CH3) ppm; C-NMR (100.62 MHz, CDCl3): δ =
173.57, 170.68, 139.45, 136.45, 132.42, 130.32, 128.8, 128.44, 81.19, 64.79, 51.51, 30.51,
28.65, 28.04 ppm; HRMS (ESI) calculated for C23H27NO4: 382.2018 [(M+H)]+, found:
382.1967 [(M+H)]+, 404.1788 [(M+Na)]+.
19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Radiochemistry
[11C]Acrylic acid 1
[11C]CO2 was transferred from the cooling trap to the reaction vessel with a helium flow of 10
mL·min-1and trapped in 100 μL of a 0.2 M solution of vinyl magnesium bromide in THF, which
was cooled to 7 °C. After 1 min, the temperature of the reaction vessel was raised to 25 °C and
maintained for 2 min. The intermediate was hydrolyzed by adding 100 μL of 2 M HCl and a
sample was taken from the solution for reverse phase HPLC analysis. RCPs were obtained in
the range of 50-70 %. The identity of the labeled compound was confirmed by co-injection with
the reference. [Rt(Grace Smart RP-18, MeCN/acetate buffer (pH 3.8) 96/4, 1 mL·min-1, 254
nm) = 13.5 min]
[11C]Methyl acrylate 2
The [11C]CO2 transfer and synthesis of the Grignard intermediate were conducted as described
above. Hydrolysis was performed with 50 μL conc. sulfuric acid and 100 μL methanol were
added. The vessel was heated to 70 °C and this temperature was maintained for 5 min while
using a helium flow of 10 mL·min-1. Then the temperature was raised to 90 °C and for a duration
of 5 min the methyl ester was distilled in a second reaction vessel cooled to -10 °C. The distillate
was diluted with 100 μL DMSO and a sample taken from the solution was analyzed by reverse
phase HPLC. The distillate was obtained in RCP range of 65-78 %. The identity of the labeled
compound was confirmed by co-injection with the cold reference. RCY obtained for this two-
step reaction is based on the quality of the first reaction and starting from approximately 2.5
GBq a d.c. isolated yield of 19 % (0.47 GBq) was accomplished with a RCP of 98 % within 20
min [Rt(Grace Smart RP-18, MeCN/water 50/50, 1 mL·min-1, 254 nm) = 4.0 min].
[11C]Tert-Butyl acrylate 3
[11C]CO2 was converted to [11C]CO on-line through reduction with molybdenum at 850 °C.
The [11C]CO was concentrated in a cold trap after removing remaining CO2 by an Ascarite
column. It was transferred with a xenon flow to a sealed reaction vial containing a solution of
Pd2[π-cinnamyl]Cl2 (3.6 mg, 7.0 μmol), xantphos (4.1 mg, 7.0 μmol), 250 μL tert-butanol and
vinyliodie (1.0 μL, 10.0 μmol) in 300 μL THF. The vial was heated for 3-5 min to 100 °C. After
cooling down, a sample was diluted with MeCN and analyzed by HPLC [Rt(Grace Smart RP-
18, MeCN/buffer 1 68/32, 1 mL·min-1, 254 nm) = 4.4 min]. The identity of the labeled
compound was confirmed by co-injection with the unlabeled tert-butyl acrylate. RCP of 70-80
20
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
% were determined with a d.c. RCY of 18 % (0.41 GBq) starting from approximately 2.5 GBq
of [11C]CO2 (AM could not be determined). [HPLC prep purification: Alltima C18 MeCN/buffer
1 70/30, 4 mL·min-1, 254 nm, Rt = 14.3 min].
[11C]N-Tritylacrylamide 4
[11C]CO was produced as described above and xenon gas was used to transfer it in a sealed
reaction vial containing a solution of Pd2[π-cinnamyl]Cl2 (3.6 mg, 7.0 μmol), xantphos (4.1 mg,
7.0 μmol), triphenylmethylamine (25 mg, 96 μmol) and vinyl iodide (1.0 μL, 10.0 μmol) in 600
μL THF. The vial was heated for 3-5 minutes to 100 °C. After it had cooled down, a sample
was taken and analyzed with HPLC [Rt(Grace Smart RP-18, MeCN/buffer 1 68/32, 1 mL·min-
1, 254 nm) = 4.5 min]. The identity of the labeled compound was confirmed by co-injection
with the cold reference compound. RCP within 75-85 % were determined with RCY of 22 %
(0.42 GBq) starting from approximately 2.5 GBq of [11C]CO2 with AM of 86-170 GBq∙μmol-1.
[HPLC prep purification: Alltima C18 MeCN/buffer 1 70/30, 4 mL·min-1, 254 nm, Rt = 9.8
min]
[11C]1-Tert-butyl 5-methyl 2-((diphenylmethylene)amino)pentanedioate 7 followed by
[11C]10
[11C]Methyl acrylate was obtained like described above. To this solution in DMSO a solution
of 5 mg (17 μmol) Schiff base precursor in 100 μL DMSO and 100 μL of a 0.1 M solution of
TBAF were added. After 5 min a sample was taken. Analysis by reverse phase HPLC and co-
injection with the cold standard confirmed product formation [Rt(Grace Smart C18,
MeCN/water 50/50, 1 mL·min-1, 254 nm) = 17.5]. For the deprotection, 50 μL of 50 % aq KOH
were added to a solution of [11C]7 in DMSO. After a couple of minutes, 200 μL concentrated
HCl were added to the vessel and the temperature was raised to 100 °C for 2 min. A sample
taken from the solution was analyzed by reverse phase HPLC (C18) as well as by chiral HPLC
[Reprosil chiral-aa, MeOH/water 70/30, 1 mL·min-1, Rt= L-Glu 7.1 min & D-Glu 11.1 min].
General procedure for the synthesis of [11C]8 and[11C]9
Synthons [11C]3 and [11C]4 were synthesized as described above. For both, the reaction mixture
in toluene was eluted through a custom made disposable celite cartridge containing
approximately 200 mg of celite, into a reaction vial containing 5 (5-10 mg, 17-33 μmol) and
10.5 equiv. of CsOH·H2O. The reaction was vigorously stirred for 5 min at 10 °C prior to
analysis. HPLC samples were taken by diluting a sample of the reaction mixture in MeCN
21
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
followed by the injection of 20 µl on the column. [Rt(Grace Smart RP-18, MeCN/buffer 1
68/32, 1 mL·min-1, 254 nm) = 10.3 min for 8, Rt = 11.5 min for 9]
General procedure for the deprotection to [11C]10 and [11C]11
For deprotecting the activating groups, the addition of 0.1 mL of 6M HCl solution to either
[11C]8 or [11C]9 and heating to 100 ºC for 2 min was sufficient. A second sample was taken for
analysis on chiral radioHPLC to determine the enantiomeric ratio of amino acid with chiral
HPLC (Reprosil chiral-aa, methanol/water 70/30, 1 mL·min-1, 214 nm for [11C]10 L-Glu Rt =
7.1 min and D-Glu 11.1 min; 90/10 for [11C]11: L-Gln Rt = 8.2 min and D-Gln 12.3 min).
22
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
References
[1] H. Lundqvist, M. Lubberink, V. Tolmachev, Eur J Phys 1998, 19, 537–552.
[2] P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem. Int. Ed. Engl. 2008, 47,
8998–9033.
[3] B. H. Rotstein, S. H. Liang, J. P. Holland, T. L. Collier, J. M. Hooker, A. A. Wilson, N.
Vasdev, Chem. Commun. 2013, 49, 5621–5629.
[4] S. Kealey, S. M. Husbands, I. Bennacef, A. D. Gee, J. Passchier, J. Label. Compd.
Radiopharm. 2014, 57, 202–208.
[5] B. H. Rotstein, S. H. Liang, M. S. Placzek, J. M. Hooker, A. A. Wilson, N. Vasdev,
Chem Soc Rev 2016, 45, 4708–4726.
[6] K. Dahl, C. Halldin, M. Schou, Clin. Transl. Imaging 2017, 5, 275.
[7] G. Antoni, B. Langstrom, Appl Radiat Isot 1992, 43, 903–905.
[8] I. Ben-David, Y. Rozen, G. Ortu, E. Mishani, Appl. Radiat. Isot. 2003, 58, 209–217.
[9] J. Eriksson, O. Åberg, B. Långström, European J. Org. Chem. 2007, 455–461.
[10] K. Dahl, M. Schou, N. Amini, C. Halldin, European J. Org. Chem. 2013, 1228–1231.
[11] J. Eriksson, J. Hoek, A. D. Windhorst, J. Label. Compd. Radiopharm. 2012, 55, 223–
228.
[12] C. Taddei, S. Bongarzone, A. K. Haji Dheere, A. D. Gee, Chem. Commun. 2015,
11795–11797.
[13] P. Nordeman, S. D. Friis, T. L. Andersen, H. Audrain, M. Larhed, T. Skrydstrup, G.
Antoni, Chem. A Eur. J. 2015, 17601–17604.
[14] C. Taddei, S. Bongarzone, A. D. Gee, Chem. - A Eur. J. 2017, 23, 7682–7685.
[15] U. Filp, A. Pekošak, A. J. Poot, A. D. Windhorst, Tetrahedron 2016, 72, 6551–6557.
[16] A. Pekošak, U. Filp, J. Škrinjar, A. J. Poot, A. D. Windhorst, Org. Biomol. Chem.
2017, 15, 570–575.
[17] A. Pekosak, B. H. Rotstein, T. L. Collier, A. D. Windhorst, N. Vasdev, A. J. Poot,
European J. Org. Chem. 2017, 1019–1024.
[18] F. Y. Zhang, E. J. Corey, Org. Lett. 2000, 2, 1097–100.
23
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
[19] T. Shibuguchi, H. Mihara, A. Kuramochi, T. Ohshima, Chem. Asian J. 2007, 794–801.
[20] A. V Mossine, A. F. Brooks, I. M. Jackson, C. A. Quesada, P. Sherman, E. L. Cole, D.
J. Donnelly, P. J. H. Scott, X. Shao, Bioconjug. Chem. 2016, 27, 1382–1389.
[21] B. Van Der Wildt, M. M. M. Wilhelmus, J. Bijkerk, L. Y. F. Haveman, E. J. M.
Kooijman, R. C. Schuit, J. G. J. M. Bol, C. A. M. Jongenelen, A. A. Lammertsma, B.
Drukarch, et al., Nucl. Med. Biol. 2016, 43, 232–242.
[22] S. Kealey, A. Gee, P. W. Miller, J. Labelled Comp. Radiopharm. 2014, 57, 195–201.
[23] T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. Engl. 2007, 46, 4222–66.
[24] K. Kato, A. B. Tsuji, T. Saga, M.-R. Zhang, Bioorg. Med. Chem. Lett. 2011, 21, 2437–
40.
[25] C. Suzuki, K. Kato, A. B. Tsuji, T. Kikuchi, M.-R. Zhang, Y. Arano, T. Saga, Bioorg.
Med. Chem. Lett. 2013, 23, 4567–70.
[26] M. J. O’Donnell, F. Delgado, C. Hostettlerl, R. Schwesinger, Tetrahedron Lett. 1998,
39, 8775–8778.
[27] B. Lygo, B. Allbutt, E. H. M. Kirton, Tetrahedron Lett. 2005, 46, 4461–4464.
[28] E. J. Corey, M. C. Noe, F. Xu, Tetrahedron Lett. 1998, 39, 5347–5350.
[29] T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine, T. Ohshima, M. Shibasaki,
Tetrahedron Lett. 2002, 43, 9539–9543.
[30] T. Ohshima, T. Shibuguchi, Y. Fukuta, M. Shibasaki, Tetrahedron 2004, 60, 7743–
7754.
[31] J. S. Bander, T. H. Lambert, J Am Chem Soc 2012, 134, 5552–5555.
[32] D. R. Reddy, M. A. Iqbal, R. L. Hudkins, P. A. Messina-Mclaughlin, J. P. Mallamo,
Tetrahedron Lett. 2002, 43, 8063–8066.
24
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700932
European Journal of Organic Chemistry
Entry for the Table of Contents
11C-Radiochemistry, Michael reaction
Ulrike Filp
Page No. – Page No.
Efficient synthesis of 11C-acrylesters,
11C-acrylamides and their application
in Michael addition reactions for PET
tracer development.
Novel Michael addition to obtain various amino acid derivatives. Online
transformations possible in carbon-11 chemistry: i) Reduction with molybdenum at
850 °C; ii) Coupling of [11C]CO2 with Vinyl-MgBr and quenching with water or
Fischer esterification; iii) Coupling of [11C]CO with Vinyl-I and Pd-xantphos with tert-
butanol or tritylamine, iv) Michael addition with base.
25
This article is protected by copyright. All rights reserved.