Negishi coupling reactions with [11C]CH3I: A versatile method for efficient 11C-C bond formation

Article abstract of DOI:10.1039/c8cc01540f

Herein, we present a fast, efficient and general one-pot method for the synthesis of ¹¹C-labelled compounds via the Negishi cross-coupling reaction. Our approach, based on the in situ formation of [¹¹C]CH₃ZnI and subsequent reaction with aryl halides or triflates, has proven efficient to synthesize [¹¹C]thymidine, a biologically relevant compound with potential applications as a proliferation marker. Theoretical calculations have shown irreversible formation of a tetracoordinated nucleophilic ¹¹C-Zn(ii) reagent and electronic requirements for an efficient Negishi coupling.

Full text of DOI:10.1039/c8cc01540f

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Negishi coupling reactions with [11C]CH3I: a
11
versatile method for efficient C–C bond
Cite this:DOI: 10.1039/c8cc01540f
formation†
Received 24th February 2018,
Accepted 26th March 2018
Luka Rejc,*a Vanessa Gomez-Vallejo,a Jesus Alcazar,b Nerea Alonso,b
´
´
´
Jose Ignacio Andres,b Ana Arrieta,c Fernando P. Cossıo
and Jordi Llop
*
c
a
´
´
´
DOI: 10.1039/c8cc01540f
rsc.li/chemcomm
Herein, we present a fast, efficient and general one-pot method for
the synthesis of 11C-labelled compounds via the Negishi cross-
coupling reaction. Our approach, based on the in situ formation
of [11C]CH3ZnI and subsequent reaction with aryl halides or triflates,
has proven efficient to synthesize [11C]thymidine, a biologically
relevant compound with potential applications as a proliferation
marker. Theoretical calculations have shown irreversible formation
of a tetracoordinated nucleophilic 11C–Zn(II) reagent and electronic
requirements for an efficient Negishi coupling.
Scheme 1 (a) [11C]methyl-arene synthesis via Stille (left) or Suzuki (right)
11C]methylation reactions; (b) two-step radiolabelling of aryl halides via
the formation of arylzinc halide and subsequent Negishi reaction with
[
Emerging applications in positron emission tomography (PET)1
have resulted in a boost in the demand for new positron-emitter-
labelled radiotracers. Carbon-11 (11C; t1/2 = 20.4 min) is one of
the most attractive positron emitters because its stable isotopes
form the main building blocks of all organic molecules, providing
an opportunity to prepare a wide variety of radiolabelled
[
11C]methyl iodide; (c) two-step one-pot reaction for [11C]methyl-arene
synthesis via Negishi cross-coupling using in situ generated 11CH3ZnI,
proposed in this study.
organic compounds through 11C-methylation, 11C-cyanation, compounds; however, the preparation, isolation, and purifica-
11C-carbonylation, and 11C-carboxylation.2 Among these, the tion of the required precursors is sometimes challenging or
most frequently used method is 11C-methylation, which encom- even impossible.5 Additionally, the Stille reaction has been found
passes a fast and efficient SN2 nucleophilic substitution reaction to result in low molar radioactivity (MA) and is hampered by the
using the easily produced labelling agent [11C]CH3I.3 However, it is biotoxicity of organotin reagents.6 The use of [11C]methyl-tin and
limited to the production of [11C]methoxides, [11C]methylamines, [11C]methyl-lithium reagents enabled [11C]methylation reactions
and [11C]methylthio compounds. Recently reported possibilities for on more accessible substrates, but the formation and manipula-
radiolabelling via palladium(0)-mediated cross-coupling reactions to tion of the organo-tin and organo-lithium compounds remains
form 11C–C bonds (Scheme 1a) do not offer a general alternative.4 challenging.7 Furthermore, strong polarisability of the C–Li
The direct 11C–C coupling between [11C]CH3I and aryl stannanes bond makes methyllithium highly nucleophilic, diminishing
or aryl boronic acids indeed results in [11C]methylaryl-based its selectivity and group tolerance.
Highly specific and versatile Negishi cross-coupling reaction
offers an alternative to 11C–C bond formation, as reported
a
´
recently (Scheme 1b).8 However, the main challenge remains
the preparation of a general [11C]methylating reagent that
would omit the preparation of aryl zincates on a case-by-case
basis. Within our tracer development program, we devised a
unique way to explore the unprecedented reaction of zinc with
[11C]CH3I to form the corresponding umpolung species
11CH3ZnI, which might enable direct [11C]methylation of aryl
halides (Scheme 1c). The fact that radiochemical reactions
proceed under pseudo-first order kinetics in the presence of a
Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Paseo Miramon 182,
´
´
20014 San Sebastian, Guipuzcoa, Spain. E-mail: jllop@cicbiomagune.es,
lrejc@cicbiomagune.es; Tel: +34 943 00 53 33
b Lead Discovery Chemistry–Discovery Sciences, Janssen Research & Development,
Jarama 75A, 45007 Toledo, Spain
c
´
Department of Organic Chemistry I, ORFEO-CINQA, Universidad del Paıs
Vasco/Euskal Herriko Unibertsitatea UPV/EHU, Donostia International Physics
´
Center (DIPC), Paseo Manuel Lardizabal 3, 20018 San Sebastian/Donostia, Spain
† Electronic supplementary information (ESI) available: Detailed experimental
details, characterization of new compounds, and computational data. See DOI:
10.1039/c8cc01540f
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Table 1 Conversion values (average values, n = 3) obtained for different
aryl halides and triflates (T = 60 1C)
clear deficiency of the labelling agent led us to hypothesise that
the reaction would proceed fast and efficiently.
Hoping to avoid notoriously long procedures of alkyl zincate
formation9 that would impact the final radiochemical yield,
we envisaged in situ [11C]CH3ZnI formation in a zinc-filled
cartridge, followed by cross-coupling with an aryl halide.10 At
the initial stage, the [11C]methylation of 4-bromoacetophenone
to produce 4-[11C]methylacetophenone was explored as a model
reaction. Due to high susceptibility of zinc to oxidation, the
metal surface was activated with an iodine solution. Iodine
rather than the traditionally used trimethylsilyl chloride was
selected because of its compatibility with the subsequent cross-
coupling reaction and the ability to form higher-order zincate
complexes, which reportedly favoured the C–C bond formation.11
N,N-Dimethylacetamide (DMA) has been used as a solvent as it
promotes the formation/improves the stability of the methyl zincate
complex and supports the transition metal-catalyzed cross-coupling
reaction. Upon activation, [11C]CH3I was directly distilled into the
cartridge. Promisingly, almost quantitative trapping of [11C]CH3I in
the cartridge (495%) could be achieved. After 1-minute reaction
at 65 1C, the contents were eluted with anhydrous DMA into a
vial pre-loaded with tetrakis(triphenylphosphine)palladium(0)
Entry
R
X
Producta (%)
1
2
3
4
5
6
7
8
4-Acetyl
3-Acetyl
2-Acetyl
Br
Br
Br
Br
Br
Br
Br
Br
I
I
I
I
I
83b
22b/35c
30b/53c
69b
4-Ethyl ester
1-Naphtyl
4-Amino
2-Amino
4-Methoxy
2,4-Dichloro
2-Acetyl
1-Naphtyl
2-Amino
4-Methoxy
4-Acetyl
21b
19b
2b
8b
9
60 (32)d
28 (21)b,d
26 (41)d
12 (28)d
33 (22)d
73b
10
11
12
13
14
15
OTf
OTf
4-Methoxy
0b
a
Calculated as the ratio between the area of the peak corresponding to
[
11C]methylaryl and the sum of the areas of all the peaks in the
b
c
radiochromatogram. Reaction time = 5 min. Reaction time of 10 min.
d
In brackets, the amount of [11C]CH3I left in the solution after reaction.
(Pd(PPh3)4) and an aryl halide (see ESI,† Fig. S1a). The reaction 4-[11C]methylacetophenone followed the expected trend with reac-
was carried out for 15 min at T = 65 1C, and the crude product tion time: the relative amount of [11C]CH3I progressively decreased,
was analyzed by high performance liquid chromatography whereas the 11C-methylated product followed an opposite trend (see
equipped with a radioactivity detector (radio-HPLC). A radio- ESI,† Fig. S2). The peak corresponding to [11C]CH4 slightly increased
active peak with a retention time (rt) of 6.2 min co-eluted with from 1 to 3 minutes, and almost disappeared at 5 minutes,
4-methylacetophenone in the UV chromatogram. The radio- completely disproving the theory of formation of [11C]CH4 during
chemical conversion, calculated as the ratio between the area the reaction and confirming the formation of the active [11C]methyl-
under the peak at rt = 6.2 min and the sum of the areas of zincate complex. Importantly, the [11C]CH3I trapping was not com-
all peaks in the chromatogram (radioactive detector), was close promised under these experimental conditions. The possibility of
to 1%. Interestingly, the highest peak in the chromatogram formation of aryl zincate, a possible by-product during the reaction,
corresponded to [11C]CH3I (rt = 4.8 min), suggesting that the acting as a nucleophile in the Negishi reaction was rejected by a
reason for the low reaction yield was the lack of formation of reverse activation experiment (Fig. S1d, ESI†). In this case, a zinc
the activated species [11C]CH3ZnI.
cartridge was preloaded with a solution of 4-bromoacetophenone
Based on a recent theoretical study on the beneficial effects and palladium catalyst, and the contents eluted to [11C]CH3I and
of Pd–Zn bond formation in oxidative addition, transmetalation, Pd(PPh3)4-filled vial after 5 minutes at 65 1C. No product was
and reductive elimination in the Negishi coupling reaction,12 the observed in the reaction mixture.
introduction of the palladium complex during [11C]methyl-zincate
To prove the generality of our method and the tolerability
formation was taken into consideration. Indeed, when Pd(PPh3)4 to a variety of functional groups, we successfully formed
(10 mmol) was added to the zinc-activating iodine solution, the 11C-labelled methyl aryls using different aryl bromides (Table 1,
chromatographic yield increased to 6% (Fig. S1b, ESI†).
entries 1–8), iodides (entries 9–13), and triflates (entries 14 and 15).
To facilitate automatisation and further increase the reaction In general, electron-withdrawing groups (EWG) (Table 1, entries 1–4)
yield, a one-pot set up was finally designed (Fig. S1c, ESI†). Herein, promoted reaction yields, whereas electron-donating group
[11C]CH3I gas was directly distilled into a zinc-filled cartridge, pre- (EDG)-bearing substrates exhibited low conversion values
loaded with a solution containing iodine, 4-bromoacetophenone, (Table 1, entries 6–8). In all the cases (entries 1–8), the relative
and Pd(PPh3)4 in anhydrous DMA, and the contents of the cartridge amount of
[
11C]CH3I remaining in the reaction crude
were eluted with anhydrous THF after 5 minutes. Moreover, two accounted for less than 5% of the total radioactivity. These
major radioactive peaks were observed in the chromatogram: the results, together with the increasing conversion values at longer
11C-methylated product, which accounted for 83% of the total reaction times (Table 1, entries 2 and 3), further support the kinetic
radioactivity (Table 1, entry 1) and a peak with an rt = 3.2 min dependency of the reaction on the ability of a substrate-palladium
identified as [11C]CH4, resulting from the immediate and quantita- complex formation/dissociation, rather than inactivation of zinc or
tive hydrolysis of [11C]CH3ZnI in the water-containing chromato- deactivation of the palladium catalyst.
graphic mobile phase. To confirm the origin of [11C]CH4, the
Surprisingly, parallel reactions with aryl iodides resulted in
reaction mixture was analyzed at 1 and 3 minutes. The relative equivalent or only slightly increased chromatographic yields.
concentration of the radioactive species [11C]CH4, [11C]CH3I, and Note that in these cases, the presence of a significant amount of
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unreacted [11C]CH3I was detected (in brackets in the table); this
suggested hampered formation of the activated 11C-methyl
zincate species. Further inspection of the UV chromatograms
revealed the presence of additional peaks, identified by GC-MS as
the de-iodinated precursor (see ESI,† Fig. S3). De-halogenation,
although seen in some aryl bromides, had a bigger effect on aryl
iodides, which readily de-halogenated in an activated zinc cartridge
at 65 1C after 10 min probably via the formation of an arylzinc
iodide complex. Similar to the detection of [11C]CH3ZnI, the
formation of arylzincates was only indirectly confirmed by
the detection of a de-halogenated product after hydrolysis.
De-halogenation yields followed the trend observed for the
oxidative addition to palladium; thus, higher de-halogenation
was observed for EWG-bearing aryl iodides.
To better understand the origins of our results, we performed
DFT calculations at the B3LYP(SCRF)-D3/6-31G(d)&LANL2DZ13
theoretical level. Both experimental and theoretical studies14
indicate that in the presence of coordinating solvents such as
THF, solvated Zn(II)-containing species are the nucleophiles
present in the Negishi coupling. In effect, our calculations show
that when DMA is used as a solvent, the reaction of [11C]CH3I
with solvated zinc yields the tetracoordinated species 1 via a
highly exergonic process (Fig. 1a). The nucleophilic intermediate
1 shows a tetrahedral coordination pattern, as expected for a d10
Zn(II) metallic centre, and enters into the catalytic cycle shown in
Fig. 1b.12,15
Fig. 1 (a) The calculated free reaction energy (B3LYP-D3(SCRF=DMA)/
6-31G(d)&LANL2DZ level of theory T = 333.15 K) associated with the
formation of nucleophile 1 from solvated Zn0ꢁ ꢁ ꢁ(DMA)4 and [11C]CH3I.
(b) Chief geometric features of tetrahedral species 1 and catalytic cycle
associated with the formation of adducts 6. The rate-determining step
leading to the reaction product via transition structure TS is highlighted in
grey and presented in more detail in Fig. 2. DMA: N,N-dimethylacetamide.
Bond distances and 11C–Zn–I bond angle are given in Å and deg.,
respectively.
333.15 K correlated with the electrophilicity of the reactants
According to this mechanism, the catalyst Pd(PPh3)2 reacts cis-5a–c estimated by means of the electrophilic local Fukui
with the alkyl halide 2 to give rise to adduct 3. This intermediate functions f + 17 calculated at the carbon atom of the aryl moiety
reacts with 1 to yield the isomeric products 5 via a quite complex involved in the formation of the Cx–11C bond (Fig. 2). In the
process in which heterobimetallic intermediates are involved. case of the formation of the adduct 6a, in which R = 4-Ac, the f +
Many previous experimental and computational mechanistic value is highest, and the associated Gibbs activation energy was
studies16 have focused on these stages of the catalytic cycle. found to be lowest. This is in good agreement with the high
Formation of both cis-5 and trans-5 is a quite fast process, yield obtained for this reaction (Table 1, entry 1). When we
the latter being even faster. However, cis-5 intermediates are analyzed the reactivity of the adducts cis-5b and c, where R =
thermodynamically more stable than their trans congeners. For 2-NH2 and R = 4-OMe, respectively (Fig. 2), we found that the local
instance, in our case, cis-5b (R = 2-NH2, see Fig. 2) is calculated to electrophilicities were negligible, and the activation energies were
be 4.1 kcal molꢀ1 more stable than trans-5b. The 11C–C bond 2.0–2.7 kcal molꢀ1 higher than that calculated for TSa. These
forming step is slower and determines the reaction rate. This higher values and the corresponding lower reaction rates are in
reductive elimination step yields adduct 6 via the saddle point line with the low yields found in the Negishi couplings between
TS, with concomitant release of the catalyst Pd(PPh3)2 and [11C]CH3I and 2-bromoaniline (Table 1, entry 7) and 1-bromo-4-
completion of the catalytic cycle (Fig. 1b).
methoxybenzene (Table 1, entry 8). Moreover, in these latter two
The energy profile associated with the cis-5 - 6 + Pd(PPh3)2 cases, the complexes 6b0 and 6c0 were found, in which the
transformation was then computed. We selected three substitu- coupling products 6b and c were bound to the catalyst by means
tion patterns a, b, and c, in which the electrophilicity of the aryl of a weak hydrogen bond and a Wheland-like interaction,
moiety varied according to the electron-withdrawing or electron- respectively. Therefore, we conclude that in the cases involving
releasing character of the R substituent. In the three cases, we electron-rich coupling products, release of the catalyst and
located three-membered cyclic transition structures TSa–c completion of the catalytic cycle can be partially hampered by
(Fig. 2) that were quite synchronous. When we computed the weak inhibition of the catalyst by the adduct generated after the
reaction profiles associated with the cis-5a - 6a + Pd(PPh3)2 reductive elimination step.
process for 12C and 13C isotopes at the methyl moiety arising
As a proof of the suitability of our method to prepare
from MeI, we obtained very similar relative Gibbs energies for biologically relevant compounds, we tackled the synthesis of
the [11C]Me and [12C]Me groups. However, a noticeable increase in [11C]thymidine (proliferation marker), starting from 5-iodo-20-
the activation free energy was computed while transitioning from deoxyuridine (Scheme 2). The synthesis resulted in a 53%
[11C]Me to [13C]Me, with DDG‡333 = DG‡333(13C) ꢀ DG‡333(11C) = radiochemical conversion in the 5 min reaction. Inclusion of
+0.3 kcal molꢀ1, which corresponded to an estimated KIE of a purification step (see ESI†) resulted in pure [11C]thymidine
ca. 1.6. We found that the computed free activation energies at with a 6.1% radiochemical yield and MA 4 50 GBq mmolꢀ1
.
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compounds, as demonstrated with the synthesis of [11C]thymidine.
Together with the development of new metal complexes, our simple
and general method provides a new alternative of 11C-radiolabelling
and may change the way of how 11C-radiochemistry can be carried
out in the future. Further applications of this approach will be
matters of future research.
Financial support for this work was provided by the Spanish
MINECO (CTQ2017-87637-R, CTQ2016-80375-P and CTQ2016-
81797-REDC) and Eusko Jaurlaritza (GV/EJ, Grant IT673-13).
Conflicts of interest
The authors declare no conflict of interest.
Notes and references
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[
11C]-complexes 1a–c. Numbers in parentheses are relative Gibbs energies
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5-iodo-20-deoxyuridine.
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