Regiospecific syntheses of functionalized diaryliodonium tosylates via [hydroxy(tosyloxy)iodo]arenes generated in situ from (diacetoxyiodo)arenes

Abstract

Ready access to (18)F-labeled aryl synthons is required for preparing novel radiotracers for molecular imaging with positron emission tomography. Diaryliodonium salts react with cyclotron-produced no-carrier-added [(18)F]fluoride ion to produce [(18)F]aryl fluorides. We aimed to prepare functionalized diaryliodonium salts to serve as potential precursors for producing useful (18)F-labeled aryl synthons, such as (18)F-labeled halomethylbenzenes, benzaldehydes, and benzoic acid esters. Such salts were designed to have one functionalized aryl ring, one relatively electron-rich ring, such as 4-methoxyphenyl or 2-thienyl, and a nonfluorine containing weakly nucleophilic anion. Generation of a [hydroxy(tosyloxy)iodo]arene from a functionalized (diacetoxyiodo)arene in situ followed by treatment with an electron-rich arene, such as anisole or thiophene, or with a functionalized arylstannane gave expedient regiospecific access to a wide range of functionally diverse diaryliodonium tosylates in moderate to high yields (44-98%). The described methodology broadens the scope for producing new functionalized diaryliodonium salts for diverse applications.

Scheme 1

General utility of diaryliodonium salts for preparing [¹⁸F]fluoroarenes from cyclotron-produced [¹⁸F]fluoride ion.

Scheme 2

Synthesis of diaryliodonium tosylates via the generation of HTIAs in situ followed by treatment with an electron-rich arene. Reagents and conditions: i) sodium perborate in MeCO₂H or peracetic acid in MeCO₂H; ii) p-TsOH·H₂O, MeCN/CHCl₃, reflux; iii) reflux.

Scheme 3

Synthesis of functionalized diaryliodonium tosylates by treating 4-[hydroxy(tosyloxy)iodo]anisole, generated in situ, with arylstannanes. Reagents and conditions: i) sodium perborate in MeCO₂H; ii) p-TsOH.H₂O, MeCN, reflux; iii) R₆Sn₂, Pd(PPh₃)₄, 1,4-dioxane, reflux; iv) CHCl₃, reflux (R = Me for 29 and R= n-Bu for 39–42).

Scheme 4

Synthesis of 2-thienylaryliodonium salts bearing an aldehyde group on the non-thienyl ring. Reagents and conditions: i) sodium perborate in MeCO₂H, 50 °C; overnight; ii) p-TsOH·H₂O, MeCN, reflux; iii) CHCl₃, reflux.