Direct C–H Radiocyanation of Arenes via Organic Photoredox Catalysis

Abstract

Innovative labeling methods to incorporate the shortlived positron emitter carbon-11( 11 C) into bioactive molecules are attractive for positron emission tomography (PET) tracer discovery. Herein, we report a direct C−H radiocyanation method that incorporates [ 11 C]cyanide ( 11 CN − ) to a series of functional electron-rich arenes via photoredox catalysis. This photoredoxmediated radiocyanation can proceed in an aerobic environment and is not moisture sensitive, which allows for ease of reaction setup and for scalable synthesis of 11 C-aryl nitriles from readily available precursors. Letter pubs.acs.org/OrgLett

Room-Temperature Copper-Mediated Radiocyanation of Aryldiazonium Salts and Aryl Iodides via Aryl Radical Intermediates

“…This approach would complement the thermal Cu-mediated radiocyanation of aryl iodides (which proceeds via concerted oxidative addition) 8 and recently reported photoredox [ 11 C]cyanations of electron-rich arenes. 34,35 With minor adjustments to the optimal conditions from Table 1 (specifically using DMF as the solvent in place of MeCN, adding PC-1, and irradiating with 395 nm LEDs), we successfully achieved the photoredox [ 11 C]cyanation of 1iodo-4-methoxybenzene to form [ 11 C]2 in 10 ± 1% RCC within 5 min at room temperature (Scheme 3B,C). While the radiochemical conversion is lower than that with the corresponding diazonium precursor, this result provides a proof of principle that a radical manifold is accessible with aryl iodides.…”

“…We reasoned that this pathway for Ar • generation could be coupled with Cu/1,10-phenanthroline-mediated Ar– 11 CN coupling to achieve the room-temperature radiocyanation of aryl iodides. This approach would complement the thermal Cu-mediated radiocyanation of aryl iodides (which proceeds via concerted oxidative addition) and recently reported photoredox [ 11 C]­cyanations of electron-rich arenes. , …”

Photocatalytic Late-Stage C–H Functionalization

“…[ 11 C]KCN from cyclotron was used in the late-stage radiocyanation of naproxen methyl ester and gemfibrozil methyl ester in 38 ± 0.4% and 27 ± 1% RCY, respectively. 214 Procter and colleagues leveraged the catalytic formation of photoabsorbing EDA-complexes between in situ generated sulfonium salts (44.3) and donor amines 44.6 to achieve the late-stage C(sp 2 )−H cyanation of arenes (44.1) with tert-butyl isocyanide 44.4 (Scheme 44). 179 Despite the early report, in 1983, of radical trapping by isocyanides to forge nitriles by Stork and co-workers, 216 this class of compounds has found little application in visible-light photocatalysis cyanation reactions.…”

“…11 C, despite its widespread use in positron emission tomography (PET), requires fast incorporation, due to its short half-life ( t 1/2 = 20.3 min). [ 11 C]­KCN from cyclotron was used in the late-stage radiocyanation of naproxen methyl ester and gemfibrozil methyl ester in 38 ± 0.4% and 27 ± 1% RCY, respectively …”

Photo- and Cu-Mediated 11C Cyanation of (Hetero)Aryl Thianthrenium Salts

“…However, these methods suffer from forcing conditions (≥100 °C) or by requiring Pd mediators, which have more stringent release criteria − (Figure A). To address these limitations, several groups have pursued alternative radical-based approaches. − For example, we recently reported a Cu-mediated, radical-based radiocyanation of aryldiazonium and aryl iodide precursors that proceeds under exceptionally mild conditions with a broad substrate scope (Figure B) . However, there are several practical and reactivity limitations associated with these aryl radical precursors.…”