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Issue 46, 2015
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An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization

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Abstract

A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [11C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (2), a highly reactive substrate 2-nitrobenzyl bromide (1) was evaluated for nucleophilic [11C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-11C]acetonitrile ([11C]-2) while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-11C]propanenitrile ([11C]-3). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-11C]indole with hydrazinium monoformate as the active reducing agent. Extensive and iterative screening of basicity, temperature and stoichiometry was required to overcome the large stoichiometry bias that favored 2-nitrobenzylbromide (1) over [11C]cyanide, which both caused further alkylation of the desired nitrile and poisoned the RANEY® Nickel catalyst. The result is an efficient two-step, streamlined method to reliably synthesize [2-11C]indole with an entire radiochemical yield of 21 ± 2.2% (n = 5, ranging from 18–24%). The radiochemical purity of the final product was >98% and specific activity was 176 ± 24.8 GBq μmol−1 (n = 5, ranging from 141–204 GBq μmol−1). The total radiosynthesis time including product purification by semi-preparative HPLC was 50–55 min from end of cyclotron bombardment.

Graphical abstract: An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization

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Publication details

The article was received on 06 Aug 2015, accepted on 18 Sep 2015 and first published on 21 Sep 2015


Article type: Paper
DOI: 10.1039/C5OB01654A
Citation: Org. Biomol. Chem., 2015,13, 11235-11243
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    An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization

    S. J. Lee, J. S. Fowler, D. Alexoff, M. Schueller, D. Kim, A. Nauth, C. Weber, S. W. Kim, J. M. Hooker, L. Ma and W. Qu, Org. Biomol. Chem., 2015, 13, 11235
    DOI: 10.1039/C5OB01654A

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