Cu(i)-mediated ¹⁸F-trifluoromethylation of arenes: Rapid synthesis of ¹⁸F-labeled trifluoromethyl arenes

Abstract

This report is concerned with an efficient, Cu(I)-mediated method for the radiosynthesis of [(18)F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three (18)F-labelled radiotracer candidates were synthesised from [(18)F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields.

Late-stage [18F]fluorination: new solutions to old problems

“…With the goal of developing methods that enable production of high specific activity trifluoromethyl groups, new approaches to both [ 18 F]alkyl- and [ 18 F]aryl-CF 3 have been reported recently. 17,18 The former can be accessed from gem -difluoro enol ethers using chemistry initially reported by Riss and colleagues. 17a,b They developed a simple and efficient procedure for the preparation of 2-[ 18 F]fluoro-2,2-difluoroethyltosylate 50 , beginning from difluorovinylsulfonate 49 (Scheme 10a), and used it as a prosthetic group for radiolabeling bioactive molecules 51 .…”

“…Reflecting this, several groups have explored copper-mediated [ 18 F]trifluoromethylation of arene and heteroarene precursors using nucleophilic fluoride recently. 18 The protocols are related, initially generating difluorocarbene, and then reacting it with [ 18 F]fluoride in the presence of a copper catalyst to prepare [ 18 F]CuCF 3 . This reactive species can then undergo cross-coupling with aryl iodides 18 or aryl boronic acids.…”

“…18 The protocols are related, initially generating difluorocarbene, and then reacting it with [ 18 F]fluoride in the presence of a copper catalyst to prepare [ 18 F]CuCF 3 . This reactive species can then undergo cross-coupling with aryl iodides 18 or aryl boronic acids. 18c The first example was reported by Gouverneur, who showed that [ 18 F]CuCF 3 could be prepared from methyl chlorodifluoroacetate using CuI, N,N,N′,N′ -tetramethylethylenediamine (TMEDA) and [ 18 F]fluoride-krytpofix-2.2.2 (K222) in DMF.…”

“…This reactive species can then undergo cross-coupling with aryl iodides 18 or aryl boronic acids. 18c The first example was reported by Gouverneur, who showed that [ 18 F]CuCF 3 could be prepared from methyl chlorodifluoroacetate using CuI, N,N,N′,N′ -tetramethylethylenediamine (TMEDA) and [ 18 F]fluoride-krytpofix-2.2.2 (K222) in DMF. 18a The resulting [ 18 F]CuCF 3 species underwent cross-coupling with a range of aryl and heteroaryl iodides in moderate to high radiochemical yields (e.g.…”

“…59 ) in good radiochemical yields (Scheme 11c). 18b The methodology was tolerant of a free phenolic functionality on the aryl iodide, although the corresponding [ 18 F]trifluoromethylated product 60 was formed in lower radiochemical yield (12%). Both Riss ( 61 ) and Gouverneur’s (not shown) one-pot methods have also been used to [ 18 F]trifluoromethylate pyrimidine-2,4(1H,3H)-diones.…”