Hypervalent aryliodine compounds as precursors for radiofluorination

Abstract

Over the last 2 decades or so, hypervalent iodine compounds, such as diaryliodonium salts and aryliodonium ylides, have emerged as useful precursors for labeling homoarenes and heteroarenes with no-carrier-added cyclotron-produced [¹⁸ F]fluoride ion (t_1/2 = 109.8 min). They permit rapid and effective radiofluorination at electron-rich as well as electron-deficient aryl rings, and often with unrestricted choice of ring position. Consequently, hypervalent aryliodine compounds have found special utility as precursors to various small-molecule ¹⁸ F-labeling synthons and to many radiotracers for biomedical imaging with positron emission tomography. This review summarizes this advance in radiofluorination chemistry, with emphasis on precursor synthesis, radiofluorination mechanism, method scope, and method application.

Keywords: PET; aryliodonium ylide; diaryliodonium salt; fluorine 18; radiofluorination; radiotracer.

FIGURE 1

Classical methods for the radiofluorination of arenes with [¹⁸F]fluoride ion and some of their limitations

FIGURE 2

Pyrolysis of diaryliodonium fluoroborates to give fluoroarenes

FIGURE 3

Yields for [¹⁸F]fluoroarenes from the radiofluorination of some simple diaryliodonium salts in acetonitrile

FIGURE 4

Exchange of axial and equatorial aryl ligands in diaryliodonium salts through pseudorotation

FIGURE 5

Examples of primary (black) and secondary (red) bonding patterns in single crystals of some aryliodine(III) compounds

FIGURE 6

Oxidative methods for preparing various substituted (diacetoxyiodo)arenes from iodoarenes

FIGURE 7

Some pathways for the synthesis of unsymmetrical diaryliodonium salts

FIGURE 8

Synthesis of phenyl(substituted-isoquinolinyl) iodonium triflates

FIGURE 9

Routes to aryliodonium ylide and spirocyclic iodonium ylides

FIGURE 10

Conventional and minimalist approaches to labeling substrates with [¹⁸F]fluoride ion

FIGURE 11

Layout of a microfluidic apparatus for the investigation of the radiofluorination of hypervalent aryliodine precursors

FIGURE 12

A pyrolytic method for the radiofluorination of diaryliodonium salts

FIGURE 13

Mechanism of the radiofluorination of unsymmetrical diaryliodonium salts

FIGURE 14

Computed transition state geometries and energies (relative to ground state) for the fluorination of a phenyl(2-tolyl)iodonium salt. TS_A leads to fluorobenzene and TS_B to 2-fluorotoluene. TS_B has somewhat lower energy (by 0.9 kcal/mol) such that 2-fluorotoluene is the preferred product. Bond distances are in Ångströms

FIGURE 15

Pyrolysis of 5-methoxy-[2.2]paracyclophane(4-anisyl)iodonium fluoride gives 3-fluoroanisole in addition to 4-fluoroanisole

FIGURE 16

Mechanism proposed for the radiofluorination of a phenyl(mesityl)iodonium salt in the presence of (MeCN)₄CuOTf in dimethylformamide

FIGURE 17

Mechanism proposed for the radiofluorination of aryliodonium ylides

FIGURE 18

Examples of compounds labeled with synthons prepared from hypervalent aryliodine precursors. Blue indicates the partial structure derived from the labeling synthon

FIGURE 19

Examples of ortho oxygen-stabilized aryliodonium ylides