PT  - JOURNAL ARTICLE
AU  - Braeden Mair
AU  - Moustafa Fouad
AU  - Uzair Ismailani
AU  - Benjamin Rotstein
TI  - Preparation of <sup>11</sup>C-amides by rhodium-catalyzed addition of organozinc iodides to <sup>11</sup>C-isocyanates
DP  - 2020 May 01
TA  - Journal of Nuclear Medicine
PG  - 64--64
VI  - 61
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/61/supplement_1/64.short
4100  - http://jnm.snmjournals.org/content/61/supplement_1/64.full
SO  - J Nucl Med2020 May 01; 61
AB  - 64Objectives: Amides are a prodigious functional group in medicinal chemistry, however many powerful and versatile synthetic strategies for their bond formation using stable isotopes prove ineffective or impractical for carbon-11. We have explored alternative methods for the generation of 11C-amides in suitable yields for radiotracer development. Methods: Initially, organozinc iodides were prepared through zinc insertions into aryl and alkyl iodides1 before undergoing rhodium-mediated reactions with substituted isocyanates to produce amide products in moderate yields (10-87%). This technique was carried out with the subsequent use of in situ prepared 11C-isocyanates2 using a Synthra MeIplus Research module for the preparation of various 11C-amides in sufficient radiochemical yields (18-99%). Results: A diverse substrate scope was prepared using aryl and alkyl organozinc iodides with a variety of substituted isocyanates, generating products with yields ranging from 10-87%. Aryl zinc iodides produced a range of products with yields from 21-87%; alkyl zinc iodides were less effective but still derived anilides in yields from 10-64%. The use of electron-withdrawing groups on the isocyanate provided superior yields (alkyl: 41-60%, aryl: 79-87%) compared to those with electron-donating groups (alkyl: 10-32%, aryl: 30-62%). Sterically hindered isocyanates could be tolerated (alkyl: 10-32%, aryl: 39-62%), as well as aliphatic isocyanates coupled with aryl zinc iodides (alkyl: 0%-Trace, aryl: 25-63%). These results informed development of the radiochemical method by harnessing derivatization with the organozinc iodide nucleophile of in situ 11C-isocyanates. Optimization was directed towards the synthesis of [11C]acetanilide, providing decay-corrected radiochemical yields of 80.9 ± 2.1%. Additional work was completed for the preparation of more complex products in sufficient yields for radiotracer development (18-99%), including [11C]propanil, and other biologically-relevant compounds. Conclusions: We have developed a radiosynthetic procedure for the preparation of 11C-amides using rhodium-catalyzed reactions between organozinc iodides and in situ prepared 11C-isocyanates. This technique provides suitable yields for continued radiotracer development. Support: NSERC RGPIN-2017-06167 References: [1] Krasovskiy, A. et al. Angew. Chem. Int. Ed. 2006, 45 (36), 6040-6044. [2] Dheere, A. K. H. et al. Chem. Commun. 2013, 49 (74), 8193-8195.