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Negishi Coupling Reactions with [ C]CH3I: a Versatile Method for Efficient 11C–C Bond Formation

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Showcasing research from Dr Jordi Llop’s laboratory at As featured in: CIC biomaGUNE, San Sebastian, Spain. 11 Negishi coupling reactions with [ C]CH3I: a versatile method for efficient 11C–C bond formation An easy, fast and efficient one-pot method allows for 11C–C 11 bond formation via in situ production of [ C]CH3ZnI, affording a wide range of functionalized [11C]methyl aryls, including [11C] thymidine, thus changing the way 11C-radiolabelling could be performed in the future. See Luka Rejc, Jordi Llop et al., Chem. Commun., 2018, 54, 4398. rsc.li/chemcomm Registered charity number: 207890 ChemComm View Article Online COMMUNICATION View Journal | View Issue 11 Negishi coupling reactions with [ C]CH3I: a versatile method for efficient 11C–C bond Cite this: Chem. Commun., 2018, 54,4398 formation† Received 24th February 2018, a a b b Accepted 26th March 2018 Luka Rejc,* Vanessa Go´mez-Vallejo, Jesu´s Alca´zar, Nerea Alonso, b c c a Jose´ Ignacio Andre´s, Ana Arrieta, Fernando P. Cossı´o and Jordi Llop * 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 11 of [ C]CH3ZnI and subsequent reaction with aryl halides or triflates, 11 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. has proven efficient to synthesize [ C]thymidine, a biologically relevant compound with potential applications as a proliferation marker. Theoretical calculations have shown irreversible formation 11 of a tetracoordinated nucleophilic C–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 Emerging applications in positron emission tomography (PET)1 the formation of arylzinc halide and subsequent Negishi reaction with have resulted in a boost in the demand for new positron-emitter- [11C]methyl iodide; (c) two-step one-pot reaction for [11C]methyl-arene 11 11 labelled radiotracers. Carbon-11 ( C; t1/2 =20.4min)isoneof synthesis via Negishi cross-coupling using in situ generated CH3ZnI, This article is licensed under a the most attractive positron emitters because its stable isotopes proposed in this study. form the main building blocks of all organic molecules, providing an opportunity to prepare a wide variety of radiolabelled 11 11 Open Access Article. Published on 17 April 2018. Downloaded 9/26/2021 10:32:28 AM. organic compounds through C-methylation, C-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 11 3 6 11 using the easily produced labelling agent [ C]CH3I. However, it is biotoxicity of organotin reagents. The use of [ C]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 11 11 The direct C–C coupling between [ C]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 Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Paseo Miramo´n 182, recently (Scheme 1b).8 However, the main challenge remains 20014 San Sebastia´n, Guipu´zcoa, Spain. E-mail: [email protected], 11 [email protected]; Tel: +34 943 00 53 33 the preparation of a general [ C]methylating reagent that b Lead Discovery Chemistry–Discovery Sciences, Janssen Research & Development, would omit the preparation of aryl zincates on a case-by-case Jarama 75A, 45007 Toledo, Spain basis. Within our tracer development program, we devised a c Department of Organic Chemistry I, ORFEO-CINQA, Universidad del Paı´s unique way to explore the unprecedented reaction of zinc with Vasco/Euskal Herriko Unibertsitatea UPV/EHU, Donostia International Physics 11 [ C]CH3I to form the corresponding umpolung species Center (DIPC), Paseo Manuel Lardizabal 3, 20018 San Sebastia´n/Donostia, Spain 11 11 † Electronic supplementary information (ESI) available: Detailed experimental CH3ZnI, which might enable direct [ C]methylation of aryl details, characterization of new compounds, and computational data. See DOI: halides (Scheme 1c). The fact that radiochemical reactions 10.1039/c8cc01540f proceed under pseudo-first order kinetics in the presence of a 4398 | Chem. Commun., 2018, 54, 4398--4401 This journal is © The Royal Society of Chemistry 2018 View Article Online Communication ChemComm clear deficiency of the labelling agent led us to hypothesise that Table 1 Conversion values (average values, n = 3) obtained for different the reaction would proceed fast and efficiently. aryl halides and triflates (T =601C) Hoping to avoid notoriously long procedures of alkyl zincate formation9 that would impact the final radiochemical yield, 11 we envisaged in situ [ C]CH3ZnI formation in a zinc-filled Entry R X Producta (%) cartridge, followed by cross-coupling with an aryl halide.10 At 11 1 4-Acetyl Br 83b the initial stage, the [ C]methylation of 4-bromoacetophenone b c 11 2 3-Acetyl Br 22 /35 to produce 4-[ C]methylacetophenone was explored as a model 3 2-Acetyl Br 30b/53c reaction. Due to high susceptibility of zinc to oxidation, the 4 4-Ethyl ester Br 69b b metal surface was activated with an iodine solution. Iodine 5 1-Naphtyl Br 21 6 4-Amino Br 19b rather than the traditionally used trimethylsilyl chloride was 7 2-Amino Br 2b selected because of its compatibility with the subsequent cross- 8 4-Methoxy Br 8b 9 2,4-Dichloro I 60 (32)d coupling reaction and the ability to form higher-order zincate b,d 11 10 2-Acetyl I 28 (21) complexes, which reportedly favoured the C–C bond formation. 11 1-Naphtyl I 26 (41)d N,N-Dimethylacetamide (DMA) has been used as a solvent as it 12 2-Amino I 12 (28)d d promotes the formation/improves the stability of the methyl zincate 13 4-Methoxy I 33 (22) 14 4-Acetyl OTf 73b complex and supports the transition metal-catalyzed cross-coupling 15 4-Methoxy OTf 0b reaction. Upon activation, [11C]CH I was directly distilled into the 3 a cartridge. Promisingly, almost quantitative trapping of [11C]CH Iin Calculated as the ratio between the area of the peak corresponding to 3 [11C]methylaryl and the sum of the areas of all the peaks in the the cartridge (495%) could be achieved. After 1-minute reaction radiochromatogram. b Reaction time = 5 min. c Reaction time of 10 min. d 11 at 65 1C, the contents were eluted with anhydrous DMA into a In brackets, the amount of [ C]CH3I left in the solution after reaction. vial pre-loaded with tetrakis(triphenylphosphine)palladium(0) 11 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. (Pd(PPh3)4) and an aryl halide (see ESI,† Fig. S1a). The reaction 4-[ C]methylacetophenone followed the expected trend with reac- 11 was carried out for 15 min at T =651C, and the crude product tion time: the relative amount of [ C]CH3I progressively decreased, was analyzed by high performance liquid chromatography whereas the 11C-methylated product followed an opposite trend (see 11 equipped with a radioactivity detector (radio-HPLC). A radio- ESI,† Fig. S2). The peak corresponding to [ C]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, 11 4-methylacetophenone in the UV chromatogram. The radio- completely disproving the theory of formation of [ C]CH4 during chemical conversion, calculated as the ratio between the area the reaction and confirming the formation of the active [11C]methyl- 11 under the peak at rt = 6.2 min and the sum of the areas of zincate complex. Importantly, the [ C]CH3Itrappingwasnotcom- all peaks in the chromatogram (radioactive detector), was close promised under these experimental conditions. The possibility of This article is licensed under a to 1%. Interestingly, the highest peak in the chromatogram formation of aryl zincate, a possible by-product during the reaction, 11 corresponded to [ C]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 11 Open Access Article. Published on 17 April 2018. Downloaded 9/26/2021 10:32:28 AM. the activated species [ C]CH3ZnI. cartridge was preloaded with a solution of 4-bromoacetophenone 11 Based on a recent theoretical study on the beneficial effects and palladium catalyst, and the contents eluted to [ C]CH3Iand 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.
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