{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T16:03:11Z","timestamp":1773244991059,"version":"3.50.1"},"reference-count":72,"publisher":"Wiley","issue":"45","license":[{"start":{"date-parts":[[2009,10,9]],"date-time":"2009-10-09T00:00:00Z","timestamp":1255046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2009,11,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The Pd<jats:sup>0<\/jats:sup>\u2010mediated rapid trapping of methyl iodide with an excess amount of a heteroaryl\u2010substituted tributylstannane has been investigated with the aim of incorporating a short\u2010lived <jats:sup>11<\/jats:sup>C\u2010labelled methyl group into the heteroaromatic carbon frameworks of important organic compounds, such as drugs with various heteroaromatic structures, in order to execute a positron emission tomography (PET) study of vital systems. The reaction was first performed by using our previously developed CH<jats:sub>3<\/jats:sub>I\/stannane\/[Pd<jats:sub>2<\/jats:sub>(dba)<jats:sub>3<\/jats:sub>]\/P(<jats:italic>o<\/jats:italic>\u2010CH<jats:sub>3<\/jats:sub>C<jats:sub>6<\/jats:sub>H<jats:sub>4<\/jats:sub>)<jats:sub>3<\/jats:sub>\/CuCl\/K<jats:sub>2<\/jats:sub>CO<jats:sub>3<\/jats:sub> (1:40:0.5:2:2:2) system in DMF at 60\u2009\u00b0C for 5\u2005min (conditions A), however, the reaction gave low yields for various heteroaromatic compounds. Increasing the amount of phosphine ligand (conditions B) led to a significant improvement in the yield, but the conditions were still not suitable for a range of basic heteroaromatic structures. Use of the CuBr\/CsF system (conditions C) also provided a result similar to that obtained under conditions B with an increased amount of the phosphine. Thus, pyridine and related heteroaromatic compounds remained less reactive substrates. The problem was overcome by replacing the DMF solvent with <jats:italic>N<\/jats:italic>\u2010methyl\u20102\u2010pyrolidinone (NMP). The reaction in NMP at 60\u2013100\u2009\u00b0C for 5\u2005min using a CH<jats:sub>3<\/jats:sub>I\/stannane\/[Pd<jats:sub>2<\/jats:sub>(dba)<jats:sub>3<\/jats:sub>]\/P(<jats:italic>o<\/jats:italic>\u2010CH<jats:sub>3<\/jats:sub>C<jats:sub>6<\/jats:sub>H<jats:sub>4<\/jats:sub>)<jats:sub>3<\/jats:sub>\/CuBr\/CsF (1:40:0.5:16:2:5) combination (conditions D) gave the methylated products in yields of more than 80\u2009% (based on the reaction of CH<jats:sub>3<\/jats:sub>I) for all of the heteroaromatic compounds listed in this study. Thus, the combined use of NMP and an increased amount of phosphine is important for promoting the reaction efficiently. The use of this general approach to rapid methylation has been well demonstrated by the synthesis of the PET tracers 2\u2010 and 3\u2010[<jats:sup>11<\/jats:sup>C]methylpyridines by using [Pd<jats:sub>2<\/jats:sub>(dba)<jats:sub>3<\/jats:sub>]\/P(<jats:italic>o<\/jats:italic>\u2010CH<jats:sub>3<\/jats:sub>C<jats:sub>6<\/jats:sub>H<jats:sub>4<\/jats:sub>)<jats:sub>3<\/jats:sub>\/CuBr\/CsF (1:16:2:5) in NMP at 60\u2009\u00b0C for 5\u2005min, which gives the desired products in HPLC analytical yields of 88 and 91\u2009%, respectively.<\/jats:p>","DOI":"10.1002\/chem.200901145","type":"journal-article","created":{"date-parts":[[2009,10,10]],"date-time":"2009-10-10T06:06:29Z","timestamp":1255154789000},"page":"12489-12495","source":"Crossref","is-referenced-by-count":27,"title":["Pd<sup>0<\/sup>\u2010Mediated Rapid Coupling between Methyl Iodide and Heteroarylstannanes: An Efficient and General Method for the Incorporation of a Positron\u2010Emitting <sup>11<\/sup>C Radionuclide into Heteroaromatic Frameworks"],"prefix":"10.1002","volume":"15","author":[{"given":"Masaaki","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Sumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Koyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"family":"Siqin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takamitsu","family":"Hosoya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misato","family":"Takashima\u2010Hirano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisashi","family":"Doi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,11,10]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"Parts\u20051\u20138:"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.19970031219"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.73.1053"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(00)00734-1"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/1099-1344(200012)43:14<1327::AID-JLCR419>3.0.CO;2-D"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1039\/b311532a"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2004.06.003"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1039\/b515215a"},{"key":"e_1_2_6_8_3","unstructured":"M.Suzuki T.Hosoya JP 2005\u2010306670 2005;"},{"key":"e_1_2_6_8_4","unstructured":"M.Suzuki T.Hosoya PCT\/JP2006\/320104 2006;"},{"key":"e_1_2_6_8_5","unstructured":"M.Suzuki T.Hosoya WO\/2007\/046258;"},{"key":"e_1_2_6_9_2","unstructured":"rapidC\u2010methylation using a boronic acid ester as the trapping agent:M.Suzuki H.Doi H.Tsukada JP 2006\u2010229169 2006;"},{"key":"e_1_2_6_9_3","unstructured":"M.Suzuki H.Doi H.Tsukada PCT\/JP2007\/066411 2007;"},{"key":"e_1_2_6_9_4","unstructured":"M.Suzuki H.Doi H.Tsukada WO\/2008\/023780 2008;"},{"key":"e_1_2_6_9_5","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200801974"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.523"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-8051(02)00315-3"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(02)00787-4"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(03)00307-9"},{"key":"e_1_2_6_14_2","first-page":"878","volume":"45","author":"Iida Y.","year":"2004","journal-title":"J. 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However it would be difficult to separate the [11C]methylated product from the large amount of remaining unreactive halide substrate see ref.\u2005[1t\u2013v]."},{"key":"e_1_2_6_40_2","unstructured":"\u00a0"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19961080326"},{"key":"e_1_2_6_41_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.199603341"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.10.5901"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.3891\/acta.chem.scand.52-0635"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1999.0722583.x"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3757(20020617)114:12<2108::AID-ANGE2108>3.0.CO;2-Z"},{"key":"e_1_2_6_45_3","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3773(20020617)41:12<2008::AID-ANIE2008>3.0.CO;2-4"},{"key":"e_1_2_6_46_2","unstructured":"The synthesis of PET tracers is rather different by usual organic synthetic methods. The reaction involves the trapping of an extremely small amount of11CH3I (approximately 100\u2005nmol of12CH3I) with a large amount (mg) of a reacting substrate. Therefore we performed the reaction by using an excess amount of an alkenylstannane with the methyl iodide."},{"key":"e_1_2_6_47_2","unstructured":"For the effect of NMP on the [Pd{P(tBu)3}2]\u2010catalyzed Stille reaction in the presence of CsF see:"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja020012f"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-1998-2135"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol0702324"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar800148f"},{"key":"e_1_2_6_52_2","unstructured":"Pyridine formed by destannylation was not observed by GC analysis."},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/om00006a053"},{"key":"e_1_2_6_54_2","unstructured":"Phosphine was limited to 16\u2005equiv in the small\u2010scale synthesis of the PET tracers due to its limited solubility. Thus the conditions defined by the use of NMP as solvent and an increased ratio of the phosphine ligand are highly tolerant and could be applied to some improved conditions in actual PET tracer synthesis as long as such required two factors are not changed."},{"key":"e_1_2_6_55_2","unstructured":"Trimethylstannane derivatives have sometimes been used as trapping substrates because of their high reactivity.[1o\u2013s]However their use has serious disadvantages from a practical point of view: 1)\u2005Tin(IV) compounds of the trimethylstannyl group are extremely toxic; 2)\u2005their reactions suffer from scrambling due to the undesired cross\u2010coupling reactions between11CH3I and (CH3)3SnR which produce highly volatile11CH3CH3which is quite dangerous for radiotracer synthesis. Such a side\u2010reaction inevitably decreases the yield and specific radioactivity of the desired labeled compound to a significant extent. Based on this information we emphasize again[1a]the fact that tributylstannane[1a\u2013g \u2009i\u2013n]or bisalkoxyborane derivatives[1h]are much better precursors for PET tracer synthesis."},{"key":"e_1_2_6_56_2","unstructured":"\u00a0"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389200003339054"},{"key":"e_1_2_6_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-003-2348-5"},{"key":"e_1_2_6_59_2","unstructured":"\u00a0"},{"key":"e_1_2_6_60_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00228-003-0643-x","volume":"59","author":"Bergstr\u00f6m M.","year":"2003","journal-title":"Eur. J. Clin. 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