Broad-scope Syntheses of [11 C/18 F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts

Abstract

Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t_1/2 =20.4 min) or fluorine-18 (t_1/2 =109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no-carrier-added [¹¹ C]CuCF₃ or [¹⁸ F]CuCF₃ . The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron-donating or electron-withdrawing groups at meta- or para- position are good to excellent (67-96 %). Ortho-substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15-34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [¹¹ C]p-trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3-trifluoromethyl-4-aminopyridine, as examples of small drug-like molecules and candidate PET radioligands, were successfully labeled in high yields (69-81 %).

Keywords: PET radiochemistry; carbon-11; diaryliodonium salts; fluorine-18; trifluoromethyl.

Figure 1.

Examples of drugs and PET radiotracers containing an aryl trifluoromethyl group.

Figure 2.

Effect of precursor amount and temperature on [¹¹C]2a yield. See SI (Table S1) for corresponding[ time-course of [¹¹C]3e yield.

Scheme 1.

Methods for bonding aryl carbon to radioactive trifluoromethyl groups.

Scheme 2.

Scope for the ¹¹C-trifluoromethylation of meta- and para-substituted aryl substrates^{[a], [b], [c]} [a] Reaction conditions: 1 (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (~ 0.5 mL). [¹¹C]CF₃H was added in DMF solution. [b] As for footnote [b] in Table 1 (n = 3). [c] The radio-HPLC yield of [¹¹C]3e is in parentheses as mean ± SD for n = 3. [d] [¹¹C]2n is the same product as [¹¹C]3b produced from 1b (Table 1). [e] The triflate salt of the precursor was used. [f] Et₃N•3HF was absent.

Scheme 3.

Scope for the ¹¹C-trifluoromethylation of ortho-substituted aryl substrates^{[a], [b], [c]} [a] Reaction conditions: 4 (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (~0.5 mL). [¹¹C]CF₃H was added in DMF solution. [b] As for footnote [b] in Table 1 (n = 3). [c] Radio-HPLC yield of [¹¹C]3e in parenthesis as mean ± SD for n = 3. [d] [¹¹C]5c is the same product as [¹¹C]3a produced from 1a (Table 1). [e] Triflate salt of the precursor was used.

Scheme 4.

Scope for the ¹¹C-trifluoromethylation of heteroaryl substrates^{[a], [b], [c]} [a] Reaction conditions: 1c, or 6a–6e (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (0.5 mL); [¹¹C]CF₃H was added in DMF solution. [b] As for footnote [b] in Table 1 (n = 3). [c] Radio-HPLC yield of [¹¹C]3e in parenthesis as mean ± SD for n = 3. [d] Iodonium salt 1c was used as precursor and the RCY in parenthesis is for [¹¹C]2a as mean ± SD for n = 3. [e] The triflate salt of the precursor was used.

Scheme 5.

Synthesis of [¹¹C]boronic acid synthons.^[a],[b],[c] [a] Reaction conditions: 8 or 10 (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (~ 0.5 mL); [¹¹C]Fluoroform was added as a DMF solution. [b] As for footnote [b] in Table 1. [c] Radio-HPLC yield of [¹¹C]3e is in parenthesis as mean ± SD for n = 3.

Scheme 6.

¹¹C-Labeling of known drugs and a PET radiotracer.^[a],[b],[c] [a] Reaction conditions: 11 or 13 or 15 (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (~0.5 mL); [¹¹C]CF₃H was added in DMF solution. [b] Radio-HPLC yield shown in green as mean ± SD for n = 3. [c] Radio-HPLC yield of [¹¹C]3e or [¹¹C]3b in parentheses as mean ± SD for n = 3. [d] n = 2.

Scheme 7.

Scope for the ¹⁸F-trifluoromethylation of aryl substrates^{[a], [b], [c]} [a] Reaction conditions: 4 (50 μmol), CuBr (5 μmol), KO^tBu (15 μmol), Et₃N•3HF (5 μmol), DMF (~0.5 mL). [¹⁸F]CHF₃ was added as DMF solution. [b] As for footnote [b] in Table 1 (n = 2). [c] Radio-HPLC yield of [¹⁸F]3e in parentheses as mean ± SD for n = 2. [d] [¹⁸F]2n is the same product as [¹¹C]3b produced from 1b (Table 1). [e] Triflate salt of the precursor was used. [f] Et₃N•3HF was absent.