An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization
Abstract
We developed a rapid method for the synthesis of carbon-11 radiolabeled indole 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 (n = 5, ranging from 141 – 204 GBq/μmol). The total radiosynthesis time including product purification by semi-preparative HPLC was 50 – 55 min from end ofmore »
- Authors:
-
- Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department
- Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department; Johannes Gutenberg Univ., Mainz (Germany). Institut fur Kernchemie
- Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department; Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (United States)
- Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1239796
- Report Number(s):
- BNL-111763-2016-JA
Journal ID: ISSN 1477-0520; OBCRAK
- Grant/Contract Number:
- SC0012704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Organic and Biomolecular Chemistry
- Additional Journal Information:
- Journal Volume: 13; Journal Issue: 46; Journal ID: ISSN 1477-0520
- Publisher:
- Royal Society of Chemistry
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; [2-¹¹C]Indole; nucleophilic [¹¹C]cyanation; Raney nickel; reductive cyclization
Citation Formats
So Jeong Lee, Fowler, Joanna S., Alexoff, David, Schueller, Michael, Kim, Dohyun, Nauth, Alexander, Weber, Carina, Kim, Sung Won, Hooker, Jacob M., Ma, Ling, and Qu, Wenchao. An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization. United States: N. p., 2015.
Web. doi:10.1039/c5ob01654a.
So Jeong Lee, Fowler, Joanna S., Alexoff, David, Schueller, Michael, Kim, Dohyun, Nauth, Alexander, Weber, Carina, Kim, Sung Won, Hooker, Jacob M., Ma, Ling, & Qu, Wenchao. An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization. United States. https://doi.org/10.1039/c5ob01654a
So Jeong Lee, Fowler, Joanna S., Alexoff, David, Schueller, Michael, Kim, Dohyun, Nauth, Alexander, Weber, Carina, Kim, Sung Won, Hooker, Jacob M., Ma, Ling, and Qu, Wenchao. Mon .
"An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization". United States. https://doi.org/10.1039/c5ob01654a. https://www.osti.gov/servlets/purl/1239796.
@article{osti_1239796,
title = {An efficient and practical synthesis of [2-11C]indole via superfast nucleophilic [11C]cyanation and RANEY® Nickel catalyzed reductive cyclization},
author = {So Jeong Lee and Fowler, Joanna S. and Alexoff, David and Schueller, Michael and Kim, Dohyun and Nauth, Alexander and Weber, Carina and Kim, Sung Won and Hooker, Jacob M. and Ma, Ling and Qu, Wenchao},
abstractNote = {We developed a rapid method for the synthesis of carbon-11 radiolabeled indole 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 (n = 5, ranging from 141 – 204 GBq/μmol). The total radiosynthesis time including product purification by semi-preparative HPLC was 50 – 55 min from end of cyclotron bombardment.},
doi = {10.1039/c5ob01654a},
journal = {Organic and Biomolecular Chemistry},
number = 46,
volume = 13,
place = {United States},
year = {Mon Sep 21 00:00:00 EDT 2015},
month = {Mon Sep 21 00:00:00 EDT 2015}
}
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Synthesis of l -[4- 11 C]Asparagine by Ring-Opening Nucleophilic 11 C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor
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