Photoinitiated Radical Carbonylation Using [11C]Carbon Monoxide : 11C-Labelling of Aliphatic Carboxylic Acids, Esters, and Amides

• Main Author: Itsenko, Oleksiy
• Format: Doctoral Thesis
• Language: English
• Published: Uppsala universitet, Kemiska institutionen 2005
• Subjects: Organic chemistry; 11C-labelling; radicals; carbonylation; carbon monoxide; solvent effects; sensitizers; sulfoxides; WAY-100635; PET; Organisk kemi
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6021; http://nbn-resolving.de/urn:isbn:91-554-6375-4

One-step photoinitiated free radical carbonylation was employed for the rapid (5–7 min) labelling of aliphatic carboxylic acids, esters, and amides with a short-lived positron emitter 11C (t½ = 20.3 min) at the carbonyl position. The labelled compounds were synthesized from alkyl iodides (0.05–0.1 mmol), [11C]carbon monoxide, and appropriate nucleophiles. Decay-corrected radiochemical yields were up to 74%; conversion of [11C]carbon monoxide reached 85–90%; specific radioactivity was 158–192 GBq/mmol. The labelled compounds were identified and characterized using HPLC, LC-MS, and 1H and 13C NMR. The effects of solvents, additives, photoirradiation, temperature, and reaction time were studied and discussed. [carbonyl-11C]Amides were synthesized using amines in 1–2 equiv. to iodides, exploiting solvent effects to control reactivity. [carboxyl-11C]Acids were synthesized using water as a nucleophile, in binary and ternary aqueous solvent mixtures; the addition of TBAOH or KOH was necessary to obtain high radiochemical yields. [carbonyl-11C]Esters were synthesized using primary and secondary alcohols, tert-butanol, and phenol. Bases were KOH, BuLi, LiHDMS. The effects of photosensitizers were studied and exploited to accelerate the labelling of carboxylic acids and esters resulting in 75–85% decay-corrected radiochemical yields under mild conditions without the use of bases. A mild procedure for the 11C-carboxylation of alkyl iodides using DMSO as an oxygen nucleophile was developed. This method is expected to be suitable in the macroscale synthesis of carboxylic acids using isotopically unmodified carbon monoxide. Radical carbonylation was applied to improve the synthesis of an extensively used PET tracer, [carbonyl-11C]WAY-100635. The tracer was synthesized in one step, whereas a common approach via Grignard reagents requires three steps. In addition, several (13C)compounds were synthesised using the described methods. Free radical carbonylation may be used for the 11C-carbonylation of alkyl iodides, whereas transition-metal carbonylation – of aryl halides and triflates. Thus, the two carbonylation methods are complementary with respect to the scope of synthetic targets.