special issue review -...

Special Issue Review

Received 12 September 2014, Revised 28 November 2014, Accepted 28 November 2014 Published online 25 February 2015 in Wiley Online Library

(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3253

Pd-mediated rapid cross-couplings using[11C]methyl iodide: groundbreaking labelingmethods in 11C radiochemistry†,‡

Hisashi Doi*

Prof. Bengt Långström is a pioneer in the field of chemistry
-driven positron emission tomography (PET) imaging. He hasdeveloped a variety of excellent radiolabeling methodologies using the methods of organic chemistry, with the aim of wideningthe potential of PET in the study of life. Among his groundbreaking achievements in 11C radiochemistry, there is the discovery ofthe Pd-mediated rapid cross-coupling reaction using [11C]methyl iodide. It was first reported by his Uppsala group in 1994–1995and was further investigated by his and other groups with a view of enhancing its generality and practicability. This reaction iscurrently considered one of the basic methods for 11C-labeling of low-weight organic compounds. This paper presents a shortsummary of the background and the development of Pd-mediated rapid cross-couplings of [11C]methyl iodide, with a focusnot only on organostannanes, but also on organoboranes, organozincs, and terminal acetylene compounds. All these reactionshave proven to be dependable 11C-labelingmethodologies that use chemically reliable carbon–carbon bond formation reactions.
Keywords: 11C-labeling; [11C]methyl iodide; Pd; cross-coupling; C–C bond formation

Labeling Chemistry Team, Division of Bio-Function Dynamics Imaging, RIKENCenter for Life Science Technologies (CLST), 6-7-3 Minatojima-minamimachi,Chuo-ku, Kobe, Hyogo 650-0047, Japan

*Correspondence to: Hisashi Doi, Labeling Chemistry Team, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST),6-7-3 Minatojima minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.E-mail: [email protected]

† This article is published in Journal of Labelled Compounds andRadiopharmaceuticals as a special issue on ‘Bengt Långström’, edited by AntonyGee, Department of Chemistry and Biology, Division of Imaging Sciences andBioengineering, Kings College London, UK and Albert Windhorst, Departmentof Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam,The Netherlands.

‡Dedicated to Prof. Dr. Bengt Långström, with deepest appreciation, to celebratehis outstanding life-long contribution to the field of radiochemistry and on theoccasion of his retirement as editor of the Journal of Labelled Compounds andRadiopharmaceuticals.

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The first Pd-mediated rapid cross-couplingsof [11C]methyl iodide with organostannanes

Prof. Bengt Långström is a Swedish chemist. He anticipated theimportance of organic chemistry for the progress of positronemission tomography (PET) imaging in the early 1970s. After over40 years of his distinguished efforts and contributions, there is nodoubt that organic chemistry has played a key role in the successof PET imaging, creating dynamic images of various biologicallyimportant molecules, in vivo, in animals and humans alike.In the synthesis of PET molecular probes, 11C with a half-life of

20.4min has been extensively used for the radiolabeling of low-molecular-weight bioactive organic compounds and drugsbecause carbon is the principal constituent in many biologicallyimportant molecules. Thus, the use of the 11C radioisotope couldessentially enable the development of various 11C-labeledprobes if the potential of organic chemistry was fully used.Among the common precursors for 11C-labeling, [11C]methyl

iodide1 has been chosen because of its high chemical reactivity. Infact, a few efficient synthetic methods were already established inthe 1970s. Prof. Långström also reported some synthetic methodsfor [11C]methyl iodide in his work as a front-line radiochemist asearly as 1976.1b) [11C]Methyl iodide can currently be automaticallysynthesized using well-established commercial radiolabelingmachines. Therefore, the development of 11C-labeling methodsusing [11C]methyl iodide can be seen as one of the fundamentallabeling technologies, with wide generality and high applicability.In the field of organic chemistry, the development of efficient

reactions for carbon–carbon bond formation is still a big challenge.So far, a number of sophisticated chemical reactions for carbon–carbon bond formation have been developed, especially in the20th century. Notably, advances in transition-metal-catalyzed cross-coupling reactions have, since the late 1960s, attracted much

J. Label Compd. Radiopharm 2015, 58 73–85

attention. This is because of their superior chemical value, stemmingfrom the fact that most of these reactions are regioselective and aretolerant of a variety of functional groups on either coupling partner.

As examples of carbon–carbon bond formation using Pd-catalyzed cross-coupling reactions between an organic halide,as electrophile, and a chemically significant substrate as thecoupling partner, we mention the Stille coupling withorganostannane,2 the Suzuki coupling with organoborane,3 theNegishi coupling with organozinc,4 the Hiyama coupling withorganosilane,5 the Hech reaction with an alkene,6 and theSonogashira coupling with a terminal alkyne.7 Actually, theNobel Prize for Chemistry in 2010 was awarded jointly to RichardF. Heck, Ei-ichi Negishi, and Akira Suzuki for contributions toPd-catalyzed cross-coupling reactions in organic synthesis.3,4,8

Copyright © 2015 John Wiley & Sons, Ltd.

Scheme 1. First report on Pd0-mediated rapid cross-coupling of [11C]methyl iodValues in parentheses indicate decay-corrected isolated yields based on [11C]met

Biography

Hisashi Doi was born in Osaka, Japan in1971. He received his PhD in 2000 fromthe Department of Chemistry at NagoyaUniversity (Professor Ryoji Noyori). From2001 to 2002, he studied PET chemistryat Uppsala University (Professor BengtLångström) as JSPS Research Fellow.He worked as technical assistant ofCreative Scientific Research Project atGifu University (Professor Masaaki Suzuki)(2003–2005) and then joined RIKENMolecular Imaging Research Program in 2005. He is currentlyserving as team leader of Labeling Chemistry Team in RIKENCenter for Life Science Technologies.

H. Doi

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On the other hand, in the field of radiolabeling chemistry, therewas little information on 11C-labeling using transition-metal-catalyzed cross-coupling methods until the mid-1990s becausethe conditions necessary for the synthesis of radiolabeledcompounds are very different from those found in ordinary organicsynthesis. The specific problems associated with 11C radiochemistryusing [11C]methyl iodide are the very small amount of radionuclideavailable (usually: 10–500nmols of [11C]methyl iodide), the shortradioactive half-life (20.4min), and the harmful radioactivity. Theseissues impose severe restrictions on the synthesis of PET probes.Generally, it is desirable to have the entire process needed to obtainan injectable solution of the 11C-labeled compound (in compliancewith the requirements for a pharmaceutical formulation) completewithin a maximum of three half-lives (i.e. 60min) because of therapid radioactive decay of 11C. This process includes the synthesisof [11C]methyl iodide starting from a 11C isotope produced by acyclotron, the 11C-labeling of the target probe, the chromatographicpurification of the desired 11C-labeled probe, and thepreparation of an injectable solution for an animal/human PETstudy. Therefore, the 11C-labeling reaction, which is the key step,must usually be completed within a time interval of 5min and isoften carried out with a large excess (μmol levels) of substrate,reagent, and catalyst to accelerate the reaction rate.

idehyl i

Joh

B. Långström et al. first reported on Pd0-mediated cross-coupling reactions of [11C]methyl iodide with organostannaneor organoborane at an international symposium in France in19949 and published their findings in a scientific journal in1995.10 As shown in Scheme 1, they demonstrated the synthesesof [11C]toluene 1, methyl 4-[11C]methylbenzoate 2, [3-11C]propene 3, and [1-11C]heptane 4 by Stille coupling or Suzukicoupling using [11C]methyl iodide. According to their report,the reactions were investigated in the presence of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] as catalyst, at 90°Cwith a very short reaction time of 4min. For example, the cross-coupling of [11C]methyl iodide with trimethylphenylstannane inDMSO gave the desired [11C]methylated compound 1 with anHPLC analytical yield of 75–85% and a 54% decay-correctedisolated yield. The use of tributylphenylstannane under the sameconditions resulted in a lower HPLC analytical yield of 40%. Theyalso reported that the reaction with tributylethenylstannane inDMSO gave the desired compound 3, with an HPLC analyticalyield of 75–85% and a decay-corrected isolated yield of 30%.Furthermore, the reaction with 9-hexyl-9-borabicyclo[3.3.1]nonane asa hexylborane substrate in benzene, 1,4-dioxane, or tetrahydrofuran(THF) gave the desired compound 4, with an HPLC analytical yieldof 60–70% and a decay-corrected isolated yield of 35%.Indeed, the publishing in 1995 of their results with cross-

coupling reactions not only encouraged PET chemists to opena new era in the field of 11C-labeling chemistry but alsogenuinely surprised the organic chemistry community with theachievement of such fast cross-couplings (with reaction timesas low as 4min) between the [11C]methyl iodide with an sp3-hybridized carbon and the stannyl or boryl substrates. This wasbecause of the fact that alkyl halides with an sp3-hybridizedcarbon represent a more difficult class of electrophiles fortransition-metal-catalyzed cross-couplings than the correspon-ding vinyl or aryl halides with sp2-hybridized carbon atoms.11

More importantly, such short reaction times were unexpectedfor most organic chemists because the reaction time fortransition-metal-catalyzed cross-couplings was generally recog-nized to be several hours at least. Prior to the research reportedby the group of Prof. Långström, the transition-metal-catalyzed

with organostannane or organoborane. (Yields were determined by HPLC analysis.odide).

n Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2015, 58 73–85

Scheme 2. Pd0-catalyzed cross-coupling of methyl iodide with alkyl-9-BBN.

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cross-couplings with alkyl halides had been reported only by M.Tamura and J. Kochi in 1971–1972,12 by A. Suzuki et al. in 1992,13

and by P. Knochel et al. in 1995.14 However, the reaction usingmethyl iodide was reported only by A. Suzuki et al. (Scheme 2).13

In addition, the difficulty of the Stille coupling between themethyl group and the aryl group was described by J. R. Nortonet al. in 1995.15 As shown in Eqns 1–3, the reaction betweenthe methyl-PdII iodide complex [trans-CH3Pd(PPh3)2I] 5,generated in the reaction of methyl iodide with Pd(PPh3)4(Eqn 1),16 and arylstannane 6, occurred very slowly with afinal yield of the coupling product of barely 3% (Eqn 2). Such alow yield was because mainly of the complicated reactionmechanism of the methyl/phenyl exchange between the Pdcomplex and the phosphine ligand (Eqn 3).15 Thus, from theperspectives of organic chemistry and organometallic chemistry,the cross-coupling reaction using methyl iodide remained a bigchallenge.Equations (1)–(3)

(1)

(2)

Scheme 3. Proposed mechanism of the cross-coupling using small amounts of [11C]

Copyright © 2015 JohnJ. Label Compd. Radiopharm 2015, 58 73–85

How did the group of Prof. Långström succeed in achievingthe cross-coupling with [11C]methyl iodide in such a shortreaction time? The most important aspect was that the PETradiolabeling conditions were very different from those usedin ordinary organic chemistry. The previously mentioneddifficulties posed by the radiolabeling conditions becameadvantageous in achieving the cross-coupling reaction. In ausual PET radiolabeling reaction, one disadvantage is the verylow concentration (usually μM level) of [11C]methyl iodide.Usually, when 40–80 nmols of [11C]methyl iodide, with aradioactivity of approximately 25 GBq and a specificradioactivity of 300–600GBq/μmol, is dissolved in 300μL ofsolvent, the concentration is calculated to be 133–266μmol/L.However, the substrate concentration in an ordinary organicchemical reaction is generally designed to be on a mM level.Such a low concentration of [11C]methyl iodide was thoughtto hinder the chemical reaction completely. There is, however,a marked advantage to the use of large excess amounts (μmollevel) of the stannyl or boryl substrate and Pd0 catalyst inovercoming the problem associated with low [11C]methyliodide concentration. The radiolabeling reaction aims at theeffective labeling of radioisotopes and does not necessarilyrequire the use of equivalent amounts of substrates or theuse of catalytic amounts (e.g. 0.1mol% relative to substrate)of catalyst that are generally used in ordinary organicreactions. If the excess substrate and catalyst do not act asinhibitors to the reaction, they could be preferentially utilizedto accelerate the reaction rate and could also allow thereaction to be completed in only one catalytic cycle(Scheme 3). From the point of view of the reaction mechanismand the kinetics of the Pd0-mediated cross-coupling reaction,the large excess of the Pd0 catalyst enables oxidative additionof the entire amount of [11C]methyl iodide to give [11C]-7,even at such low concentration levels. The large excess of

(3)

methyl iodide under the conditions of large excess of Pd catalyst and substrate.

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Scheme 4. Pd0-mediated rapid cross-coupling of methyl iodide with excessamount of tributylphenylstannane.

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stannyl or boryl substrate can accelerate the transmetalationbetween [11C]-7 and the substrate, to give [11C]-8 (Scheme 3).The oxidative addition or transmetalation step has often beenconsidered the rate-determining step in Pd-catalyzedreactions.17 Fortunately, the primary carbon atom of methyliodide undergoes oxidative addition much more easily thanother alkyl halides if the reaction proceeds via an SN2 typemechanism by the attack of Pd0 on the sp3-hybridized carbonin the alkyl iodide.17

In conclusion, in the field of PET radiolabeling chemistry,the large excess of substrate and Pd catalyst can overcomethe problem of long reaction times in the rate-determiningstep. It can also minimize the number of catalytic cyclesrequired, thereby reducing the dependency on factors suchas turn over frequency and turn over number. These factorseventually result in cross-coupling reactions using [11C]methyliodide occurring within very short reaction times of severalminutes.

Even from the point of view of the reaction mechanism, theresearch approach used by the group of Prof. Långström favoredthe requirements for the synthesis of 11C-labeled PET probe. Assuch, their achievement has become the first actual success of11C-labeling by C–11C bond formation via the Pd-mediatedcross-coupling method. This method has often been referred toas the Pd-mediated rapid C-[11C]methylation.

The discovery of Pd-mediated rapidcross-coupling of [11C]methyl iodide witharyltributylstannane

The group led by M. Suzuki succeeded in developing 15R-TIC 9,which is a prostaglandin ligand selectively responsive to aprostacyclin receptor in the central nervous system.18 The tolylgroup in 9 was intended as a trigger component to create aPET molecular probe by labeling with a [11C]methyl group viaStille coupling with [11C]methyl iodide. For this purpose, atributylstannyl precursor 10 was selected to avoid the problemof high toxicity associated with trimethylstannyl compounds.According to previous research by the group led by Prof.Långström, the cross-coupling of [11C]methyl iodide withtributylphenylstannane revealed that the reaction was very slowcompared with the reaction with trimethylphenylstannane10 andthat the method actually hampered the incorporation of a [11C]methyl group into 9 by the cross-coupling between [11C]methyliodide and 10. These problems prompted the search for adifferent and faster cross-coupling reaction between methyliodide and various aryltributylstannanes.19

The coupling reaction was first investigated using a large excess(40:1) of tributylphenylstannane 11 relative to methyl iodide,under normal organic chemistry conditions (Scheme 4). After

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carrying out a number of experiments at a fixed reaction time of5min, the optimal conditions for Stille methylation were foundto be the use of a stoichiometric mixture of [Pd{P(o-tolyl)3}2]/CuCl/K2CO3.

19

For example, the use of a coordinatively unsaturated Pd0

complex, generated in situ from Pd2(dba)3(dba: dibenzyli-deneacetone) and P(o-tolyl)3 (1:4) in the presence of CuCl andK2CO3 in DMF at 60°C, was found to be highly efficient, yieldingthe desired toluene derivative in 91% yield (based on methyliodide). Both CuCl (or CuBr) and K2CO3 were necessary, but CuIwas ineffective. Notably, the reaction between methyl iodideand trimethylphenylstannane led to toluene in >100% yield(122–129%) together with ethane. This indicated that anunexpected cross-coupling reaction between the phenyl groupand the methyl group on the Sn atom was contaminating theproduct to a considerable extent, interfering with the methylgroup of the desired toluene product. The result showed thatthe participation of the methyl group on the Sn atom in thereaction with methyl iodide could not be avoided.20 It alsoshowed that the reaction of [11C]methyl iodide witharyltrimethylstannane led to a low specific radioactivity of the[11C]methylated arene product, as a result of scramblingbetween the [11C]methyl group from [11C]methyl iodide andthe methyl group from trimethylstannane.21,22 Thus,aryltributylstannanes appeared to be better suited as substratesfor the Stille methylation than the aryltrimethylstannanes.The coupling of methyl iodide with tributylphenylstannane

probably proceeds by the mechanism proposed in Eqns 4–7,where X= Cl or Br and M= Sn(n-C4H9)3 or Cu{P(o-tolyl)3}. In thefirst step, methyl iodide undergoes oxidative addition with aPd0 species to generate methyl–PdII iodide 12 (Eqn 4). The PdII

complex 12 may react directly with the stannyl compound 11,to afford the (methyl)(phenyl)PdII complex 13 (Eqn 6). However,the formation of the latter would be facilitated by thephenylcopper compound 14, formed by prior Sn/Cutransmetalation23 (Eqn 5). Finally, toluene is formed by reductiveelimination from the PdII complex 13 (Eqn 7). The P(o-tolyl)3ligand, with its great bulkiness (cone angle of 194°24), facilitatesthe generation of the coordinatively unsaturated Pd0 and PdII

intermediates.25 Transmetalation to give 13 and/or reductiveelimination of toluene requires the formation of thetricoordinated PdII complex.26 DMF may help stabilize such Pdintermediates. The presence of K2CO3 may help convert thestannyl halide 15a or 15b from a side product into a stabletributylstannylcarbonate.27

Equations (4)–(7)

(4)

(5)


Scheme 5. Synthesis of 15R-[11C]TIC methyl ester [11C]-16 by Pd0-mediated rapid C-[11C]methylation.

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This thorough research of the cross-coupling of methyliodide and tributylphenylstannane was reported in 1997 bythe group led by M. Suzuki and also comprising Prof.Långström, Y. Watanabe, and R. Noyori (a Nobel laureate inChemistry 2001), et al.19

The synthesis of 11C-labeled 15R-TIC methyl ester28 [11C]-16using [11C]methyl iodide and stannane 10 was conducted inthe presence of the mixture of Pd2(dba)3/P(o-tolyl)3/CuCl/K2CO3

in DMF at 60–70°C for 5min in the laboratory of Prof. Långström,at the PET Centre of Uppsala University (Scheme 5). However, thePd0-mediated rapid C-[11C]methylation under PET radiolabelingconditions lacked reproducibility for some unknown reasons.Attempts to overcome this difficulty focused on the problemcaused by CuI because the use of CuI severely retarded themodel methylation of tributylphenylstannane.19 This was

(6)

(7)

Scheme 6. Two-pot stepwise procedure for efficient synthesis of 15R-[11C]TIC met


because the quality of [11C]methyl iodide varied slightly fromsystem to system, and first suspicions were of contamination ofthe iodine sources such as HI or I2.

In the commonly used automated radiolabeling systems,[11C]methyl iodide is produced by the reduction of [11C]CO2

with LiAlH4 and the subsequent iodination with hydroiodicacid.1,29 As another method, direct iodination of [11C]CH4 withI2 is often used for the synthesis of [11C]methyl iodide withhigher specific radioactivity.30 The [11C]methyl iodide (b.p.42°C) obtained by the former procedure was transferred tothe main reaction vessel for [11C]methylation using a N2 (orHe) gas flow, while the original reaction vessel where [11C]methyl iodide was produced was heated above 120°C. Acartridge of Ascarite was used to trap the unreacted [11C]CO2 and the gaseous HI, while a cartridge of P4O10 was usedto trap the H2O from the first vessel into a second vessel.However, the [11C]methyl iodide produced did not alwayshave a high purity, and contamination of iodine sourceswas presumed in some cases. Such contamination isdetrimental to organometallic reactions such as the Pd-mediatedrapid C-[11C]methylation. If the reaction mixture contains CuI saltas an additive, there is the possibility of generating CuI that actsas an inhibitor to the reaction.

Therefore, in order to minimize the inhibitory effect of CuI, atwo-pot stepwise procedure was introduced for the synthesisof the PET probe [11C]-16 (Scheme 6).31 This procedureinvolves the independent synthesis of a [11C]methylpalladium

hyl ester [11C]-16.


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complex in reaction vessel (A) and a phenyl copper complexin reaction vessel (B) at room temperature (25°C), followedby reacting these two compounds at a higher temperature(60–70°C, 5min). The two-pot stepwise procedure providesother benefits such as the following: (1) when adding [11C]methyl iodide through a N2 (or He) gas flow in the reactionvessel (A), the large excess amounts of Pd0 and phosphinecan trap the impurities from the iodine sources such as HIor I2. (2) In the case of substrates with NH2, OH, or SHfunctional groups, the SN2 reaction between [11C]methyliodide and such groups can be avoided because all the [11C]methyl iodide has already reacted with the Pd0 species inthe reaction vessel (A).

Thus, the highly specific PET probe, the 15R-TIC methyl ester[11C]-16, was obtained with high reproducibility and possesseda sufficient radioactivity of 2–3GBq. The decay-correctedradiochemical yield was 30–85% based on [11C]methyl iodide.The radiochemical and chemical purities were more than 98%,and the total synthesis time was 35–40min. The quality of[11C]-16 was proven to be high enough for use in a human PETstudy. After obtaining approval from the ethics committee,human PET studies were initiated. The first trial took place inProf. Långström’s laboratory at the Uppsala University PETCentre in June 2000, and PET imaging of [11C]-16 in the humanbrain was carried out.32 In addition, PET imaging of hepatobiliarytransport in animals and humans has been investigated using[11C]-16.33 This research was considered a successful exampleof interdisciplinary collaboration of chemistry, biology, andmedicine.

The same method was successfully applied to the synthesis ofa 11C-labeled prostaglandin F2α analogue 17, in the samecollaborative relationship.34 Since then, the Pd0-mediated rapidC-[11C]methylation using organostannane has evolved from theintroduction of the [11C]methyl group on the phenyl ring towardits insertion in heteroaromatic,35 vinyl,36 and acetyl37

substituents. The optimized reaction conditions have beenapplied to the synthesis of PET probes with biologicalimportance such as the [methyl-11C]thymidine 18,38 4′-[methyl-11C]thiothymidine 19,38,39 [11C]zidovudine 20,40 [11C]stavudine 21,40 [11C]telbivudine 22,40 [11C]H-1152 23,41 and the11C-labeled GN8 derivative 24.42 The congeneric or improvedreaction conditions have been adopted by the wider PETchemistry community for the synthesis of important PET probesusing the corresponding organostannane substrate, forcompounds such as [p-11C-methyl]MADAM 25,43 5-[11C]methyl-6-nitroquipazine 26,44 [11C]toluene 27,45 5-[11C]methyl-A-8538028,46 4-[11C]methylmetaraminol 29,47 [11C]FMAU 30,21 11C-labeled citalopam analogue 31,22 11C-labeled mGlu1 antagonistprobe 32,48 [11C]celecoxib 33,49 [11C]M-MTEB 34,50 [11C]MPEP35,51 [11C]SB 222200 36,52 (–)-[11C]OMV 37,53 11C-labeledreboxetine analogues 3854 and 39,54 [11C]CHIBA-1001 40,55

[11C]FTIMD 41,56 [11C]metrazoline 42,57 [11C]TEIMD 43,57 and[11C]ITDM 44.58


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Scheme 7. Pd-mediated rapid cross-coupling of [11C]methyl iodide with organobora

Pd-mediated rapid cross-coupling of[11C]methyl iodide with organoborane

The Suzuki coupling uses boron substrates, which are less toxicthan the tin substrates used in the Stille coupling. Because thechemically synthesized PET probe must be strictly purified usingHPLC or other methods, the use of a less toxic substrate ispreferable if the probe is to be used in animal or human PETstudies.In the case of Suzuki coupling, the cross-coupling of methyl

iodide with an alkylborane was realized in 1992 by the researchgroup of A. Suzuki (Scheme 2).13 The reaction of methyl iodidewith arylboranes was also reported in 2004 by L. J. Gooβen.59

However, the chemically valuable C(sp3)–11C(sp3) couplings inthe initial phase of the Suzuki coupling using [11C]methyliodide under PET radiolabeling conditions were alreadyreported in 1995 and 1998 by the group of Prof. Långström(the synthesis of [1-11C]heptane 4)10 and the group of E. D.Hostetler and J. A. Katzenellenborgen (the synthesis of[ω-11C]palmitic acid 45),60 respectively. They bothaccomplished the synthesis without the problem of β-hydrogen elimination, often found in Pd chemistry. Thereaction of [11C]methyl iodide with benzylborane wasreported as another example of C(sp3)–11C(sp3) coupling forthe purpose of incorporation of a [11C]methyl group into analkyl structure.61 These successes are mainly because of thefact that the organoborane has relatively high reactivity in thecross-coupling reaction in the presence of a base or a fluoride anion.

The investigation of Pd-mediated rapid C-[11C]methylationof a phenyl group via Suzuki coupling using [11C]methyl iodidewas first reported in 2005 by the Merck group led by E. D.Hostetler (Scheme 7).62 The synthesis of [11C]toluenederivatives was achieved through the reaction of [11C]methyliodide with arylboranes in the presence of [Pd(dppf)Cl2](dppf = 1,1′-bis(diphenylphosphino)ferrocene) and K3PO4 inDMF under microwave heating.62 Surprisingly, the reactiongave the desired [11C]methylated products in high yield(decay-corrected isolated yield: up to 92%) and was completedwithin a very short time (90 s), largely because of the heatingefficiency of the microwave. This excellent method wasapplied to the synthesis of the mGluR5 PET probe, [11C]M-MTEB 34 (Scheme 8).50

In contrast, the group of M. Suzuki reported a Pd0-mediatedrapid C-methylation with organoboranes using a conventionalthermal heating method in 2009 (Scheme 9).63 The couplingreaction of methyl iodide with pinacol phenylboronatewas investigated under standard organic chemistryconditions. The mixture of Pd2(dba)3/P(o-tolyl)3/K2CO3 (1:4:4)

ne using microwave heating.


Scheme 8. Synthesis of [11C]M-MTEB 34 by the Suzuki coupling using microwave heating.

Scheme 9. Pd0-mediated rapid cross-coupling of methyl iodide withorganoborane by conventional thermal heating.

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in DMF or DMF/H2O (9:1) was found to be effective for themethylation.63 The reaction also proved applicable to various typesof aryl and alkenyl boranes, giving the corresponding methylatedderivatives in high yield (80–99%). The E and Z olefinicstereoisomers yielded their corresponding methylated productswith the retention of stereochemistry.63 The actual C-[11C]methylation using a mixture of Pd2(dba)3/P(o-tolyl)3/K2CO3 inDMF or DMF/H2O was demonstrated in the synthesis of11C-labeled celecoxib 33,64 PSPA-4 46,65 dehydropravastatin47,66 cetrozole 48,67 and ATRA 49.68 The group of J. L.Kristensen investigated the reaction conditions for C-[11C]methylation of para-aminoarenes and eventually succeeded inthe synthesis of 11C-labeled CIMBI-712 50 (Scheme 10).69 Theyalso reported the 11C-labeling of vortioxetine 51 by the Suzukicoupling method.70

Slightly improved conditions comprising a 1:3 ratio ofPd/P(o-tolyl)3 was also found to be applicable to the C-fluoromethylation using the reaction of fluoromethyl iodide(FCH2I) with pinacol phenylboronate.63 Further modifiedconditions enabled rapid C-[18F]fluoromethylation of arenesunder PET radiolabeling conditions (Scheme 11).71

Scheme 10. Synthesis of 11C-labeled CIMBI-712 50 by the Suzuki coupling.

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Scheme 11. Pd0-mediated C-[18F]fluoromethylation using [18F]fluoromethyl halide.

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Pd-mediated rapid cross-coupling of[11C]methyl iodide with organozincs

Organozincs are one of the most reactive nucleophiles in Pd-catalyzed cross-coupling reactions, allowing rapid trans-metalation between PdII and the organozinc substrate.Therefore, the Negishi coupling often succeeds where othercoupling reactions such as the Stille coupling and the Suzukicoupling fail. However, compared with organostannane ororganoborane, organozinc substrates are often incompatiblewith common functional groups (e.g. OH, SH, COOH, CHO, etc.)and there are some real limitations to their synthetic use as aresult of their sensitivity to water and air. These matters havehampered the realization of the Negishi coupling under PETradiolabeling conditions until relatively recently.

In 2013, the KCL group of S. Kealey, J. Passchier, and M. Huibanreported the Pd-mediated rapid cross-coupling of [11C]methyliodide with organozinc for the first time in the field of PET chemistry(Scheme 12).72 They accomplished rapid C-[11C]methylations ofseveral aryl compounds via the Negishi coupling of [11C]methyliodide with arylzinc iodide prepared from aryl iodide and Rieke zinc.The conditions used, namely Pd(PPh3)Cl2 in dimethylacetamide for5min at room temperature or elevated temperature (110–120°C),led to the desired [11C]methylated arenes with a very highradiochemical yield of up to 99%.72 In the representative synthesisof 1-[11C]methylnaphthalene, the decay-corrected isolated yieldwas 62% after purification by semi-preparative HPLC. By applyingthis method, they succeeded in synthesizing 11C-labeled MPEP 35as a mGluR5 antagonist with satisfying radioactivity and purity, witha total synthesis time of 32±1min (Scheme 13).72

In 2001–2002, P. Knochel et al.73 reported solid and stableorganozinc reagents for Negishi coupling. These reagents canovercome the problems of sensitivity to air and moisture ofcommon organometallics used in the Negishi coupling. Such

Scheme 13. Synthesis of 11C-labeled MPEP 35 by the Negishi coupling.

Scheme 12. Pd-mediated rapid cross-coupling of [11C]methyl iodide with organozin


stable organozinc reagents are expected to promote the utilizationof the Negishi coupling in PET probe synthesis in the near future.

The Sonogashira-type cross-coupling of[11C]methyl iodide with terminal alkyne

The C(sp)–11C(sp3) bond-forming rapid C-[11C]methylation via theSonogashira coupling method using [11C]methyl iodide was firstreported in 2003 by the group of F. Wuest.74 They investigatedthe Pd0-mediated reaction conditions of [11C]methyl iodide withmestranol 52 for the synthesis of the [11C]methyl-incorporatedcompound 17α-(3′-[11C]prop-1-yn-1-yl)-3-methoxy-3,17β-estradiol53 (Scheme 14).74 After a number of experiments, the combinedsystem of Pd2(dba)3/AsPh3/tetrabutylammonium fluoride (TBAF)in THF, in the absence of CuI as co-catalyst, was found to beeffective for the coupling reaction, giving the desired compound53 with a 27–47% decay-corrected isolated yield, with a reactiontime of 21–27min.74 Obviously, this labeling method will be moreappropriate for the incorporation of [11C]methyl groups intoterminal alkynes as a result of the direct use of an alkynyl substrate.

Perspectives

Several different types of Pd-mediated rapid C-[11C]methylationsusing [11C]methyl iodide have been realized over the past20 years. Each reaction has each its own strengths andweaknesses in relation to the preparation of a 11C-labeled PETprobe. It is therefore necessary to decide which type of rapidC-[11C]methylation is suitable for the synthesis of the targetPET probe. In the succeeding texts, my personal views andperspectives about the three types of Pd-mediated rapidC-[11C]methylations are described, (namely, the Stillecoupling, the Suzuki coupling, and the Negishi coupling) inthe hope that in the future, these marvelous 11C-labeling

c.


Scheme 14. Pd0-mediated rapid cross-coupling of [11C]methyl iodide with terminal alkyne of mestranol 52.

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methods will be much more widely utilized in the field of PETchemistry.Regarding the Stille coupling, one of the most significant

features is the high functional group tolerance. Moreover, thepreparation of stannyl substrates used in the Stille coupling hasbeen well established, and the substrates are air andmoisture stable. The low polarity of stannyl substrates isoften preferable in regards to purification of the desiredPET probe by reversed-phase HPLC. This is because of thelarge difference in polarity compared with other reagentsand reactants used in the reaction. Taking these factors intoaccount, the Stille-type rapid C-[11C]methylation would berecommended as a first-line 11C-labeling method from acomprehensive standpoint. However, it should be notedthat there are two major drawbacks to this route, firstly,the toxicity of the stannyl compounds, and secondly, thefact that the Stille coupling is poorly suited for alkyl–alkylcoupling.In contrast, the boryl substrates used in the Suzuki coupling

exhibit low toxicity and are generally stable. Methods ofpreparation of organoborane compounds are also wellestablished. The compounds are generally insensitive to waterand are compatible with most organic functional groups. TheSuzuki coupling has also been used for alkyl–alkyl coupling,and new developments and refinements are being reportedfrequently. Recent advances and improvements in the Suzukicoupling may lead to it exhibiting even greater versatility whilealso overcoming some of the weaknesses observed in the Stillecoupling technique. Currently, one of the main points ofdiscussion between PET chemists relates to the fact that Pd-mediated rapid C-[11C]methylations by Suzuki coupling oftenshow higher reactivity compared with the Stille coupling. Thereport by L. Kristensen et al.69a) will be helpful in deciding theoptimal conditions for 11C-labeling of new compounds usingthe Suzuki-type rapid C-[11C]methylation.On the other hand, the Negishi coupling reaction, which

makes use of organozinc substrates, displays excellentreactivity but relatively less functional compatibility comparedwith other cross-coupling reactions. In general, organozincsubstrates, many of which cannot be stored for long periodsof time, should be prepared in situ under an inert atmosphereof nitrogen or argon just prior to carrying out the Pd-mediatedrapid C-[11C]methylation. At present, there are very fewpractical demonstrations of the synthesis of 11C-labeled PETprobes via the Negishi-type rapid C-[11C]methylation. However,in the future, this method will likely be proven to be a usefulalternative to the Stille and Suzuki couplings through anincrease literature volume relating to the Negishi-type rapidC-[11C]methylation.In terms of medical studies, many PET probes synthesized

by Pd-mediated rapid C-[11C]methylations have been usedin human PET studies after confirming their quality. In the


future, strict analysis of possible metal contamination in theinjectable solution will also be required, especially withregard to any PET probes synthesized via Pd-mediated rapidC-[11C]methylations. In order to guarantee the quality of thePET probes, the use of inductively coupled plasma massspectrometry (ICP-MS) will be essential, as it is one of fewanalytical techniques that are capable of detecting metalsat ppb to ppt level.

Conclusions

This paper concentrated on the development of Pd-mediatedrapid cross-coupling reactions of [11C]methyl iodide withorganostannanes, organoboranes, organozincs, and terminalacetylene compounds, which led to the synthesis of biologicallyor pharmaceutically significant PET probes. Indeed, there aremany other attractive 11C-labeling methods that involve Pd-mediated cross-coupling using [11C]methyl iodide. In particular,the reaction of [11C]methyl iodide with alkenyl zirconocene75

and the reaction of organohalides with [11C]methylstannanesderived from [11C]methyl iodide76 are highly valued as newapproaches to rapid C-[11C]methylation. These 11C-labelingmethods are expected to be utilized for PET probe synthesis inthe future. In this paper, I also describe the developmentalprocess, background, and insight into the reaction, as much aspossible, especially with regard to the rapid cross-couplingstudies of which I have been a part. Regarding the transition-metal-mediated C-[11C]methylation using [11C]methyl iodide, itis worth mentioning that other 11C-labeling methods based onorganocopper chemistry have been developed for the synthesisof 11C-labeled fatty acids.77

Going back to the history of 11C radiochemistry, thepioneering works and significant contributions of Prof.Långström have opened up a new era of 11C-labelingmethods involving Pd-mediated rapid C-[11C]methylation, asdescribed in this paper. He has driven forward manycollaborative works with world famous scientists andnurtured many PET chemists currently at the forefront ofPET research around the world. He is, very deservedly, called‘The Father of PET Chemistry’.

Acknowledgements

I would like to express my heartfelt gratitude to Prof. Dr. AntonyGee and Dr. Albert Windhorst, editors of this special issue, forgiving me an opportunity to summarize Pd-mediated rapidC-[11C]methylations. I also want to thank my amazing universityprofessors, Prof. Dr. Masaaki Suzuki, Prof. Dr. Ryoji Noyori, Prof.Dr. Bengt Långström, and Prof. Dr. Yasuyoshi Watanabe, fromwhom I learned organic chemistry, PET chemistry, and medicalresearch.


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