Palladium(0)‐Mediated Rapid Methylation and Fluoromethylation on Carbon Frameworks by Reacting Methyl and Fluoromethyl Iodide with Aryl and Alkenyl Boronic Acid Esters: Useful for the Synthesis of [¹¹C]CH₃C‐ and [¹⁸F]FCH₂C‐Containing PET Tracers (PET=Positron Emission Tomography)

Abstract

A new synthetic methodology for the rapid methylation and fluoromethylation on aryl and alkenyl frameworks by using methyl and fluoromethyl iodide with an organoboronic acid ester has been developed under the simple and mild conditions of [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/K(2)CO(3) (dba= dibenzylideneacetone) in DMF at 60 degrees C for 5 min (see scheme). This boron protocol provides a firm chemical basis for the synthesis of (11)C- and (18)F-incorporated PET tracers.The rapid methylation and fluoromethylation on aryl and alkenyl carbon frameworks by reacting methyl and fluoromethyl iodide with aryl and alkenyl boronates have been studied with the focus on the realization of the synthesis of [(11)C]CH(3)- and [(18)F]FCH(2)-labeled positron emission tomography (PET) tracers. The coupling of methyl iodide and pinacol phenylboronate (40 equiv) is accomplished in >91 % yield within 5 min at 60 degrees C under the conditions of [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/K(2)CO(3) (0.5:2:2; dba=dibenzylideneacetone) in DMF. The reaction shows a high generality and is applicable to various types of aryl and alkenyl boronates, giving the corresponding methylated derivatives in high yields (80-99 %). This reaction is also useful for the rapid incorporation of the fluoromethyl group. Thus, this boron protocol provides a firm chemical basis for the synthesis of (11)C- and (18)F-incorporated PET tracers and can be used as a complementary method for [(11)C]methylation together with our previous and ongoing processes using organotributylstannanes.

Evaluation of TlOH Effect for Pd<sup>0</sup>-Mediated Cross-Coupling of Methyl Iodide and Excess Boronic Acid Ester toward Fabrication of [<sup>11</sup>C]CH<sub>3</sub>-Incorporated PET Tracer

“…Such a strong base may also be detrimental for base-sensitive substrates. The results presented herein serve as a confirmation that the conditions described in our previous Pd 0 -mediated rapid C-methylation studies [5][6][7][8] are currently the most efficient [3,9]. The four novel types of rapid C-methylations discussed above are potential groundbreaking methods for fabricating short-lived 11 C-incorporated PET probes for in vivo molecular imaging studies in both animals and humans.…”

“…For the actual PET tracer synthesis, we set up a model reaction using excess boronic acid pinacol ester for methyl iodide (40 equiv) [6][7][8]. The reaction time was fixed at 5 min, which is similar to our previous studies using organoborane compounds [7,8].…”

“…The reaction time was fixed at 5 min, which is similar to our previous studies using organoborane compounds [7,8]. First, we attempted Kishi's conditions that involve the reaction of phenylboronic acid pinacol ester (1a) under CH 3 I/1a/[Pd{P(C 6 H 5 ) 3 } 4 ]/ TlOH (1:40:1:3) in 90:10 THF/H 2 O at RT for 5 min [3].…”

“…Four types of rapid cross-coupling reactions (rapid C- [ 11 C]methylations) were developed for arene, alkene, alkyne, and alkane frameworks using [ 11 C]methyl iodide and excess amounts of organostannyl and organoborane substrates [5]. Pd 0 -mediated Suzuki-Miyaura-type rapid C-methylations were conducted using methyl iodide and a phenyl- [6], an alkenyl- [7] a benzyl- [8], or a cinnamylboronic acid ester [8] 3 and CsF. These conditions are superior to the method using [Pd(dppf)Cl 2 ] (dppf = 1,1'-bis(diphenylphosphino)ferrocene) and K 3 PO 4 under microwave heating [9].…”

11C-Cetrozole: An Improved C-11C-Methylated PET Probe for Aromatase Imaging in the Brain

“…1) 11 C-carbon dioxide was produced by a 14 N(p,a) 11 C reaction using a cyclotron (CYPRIS HM-18; Sumitomo Heavy Industries Ltd.) and then converted to 11 C-methyl iodide by treatment with lithium aluminum hydride, followed by hydriodic acid. The obtained 11 C-methyl iodide was used for palladium(0)-mediated rapid 11 C-methylation as follows (26).…”