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

Journal Article · · Organic and Biomolecular Chemistry
DOI:https://doi.org/10.1039/c5ob01654a· OSTI ID:1239796
 [1];  [1];  [1];  [1];  [2];  [2];  [1];  [3];  [4];  [1]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department; Johannes Gutenberg Univ., Mainz (Germany). Institut fur Kernchemie
  3. Brookhaven National Lab. (BNL), Upton, NY (United States). Biological, Environmental & Climate Sciences Department; Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (United States)
  4. Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (United States)
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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.

Research Organization:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
SC0012704
OSTI ID:
1239796
Report Number(s):
BNL-111763-2016-JA; OBCRAK
Journal Information:
Organic and Biomolecular Chemistry, Vol. 13, Issue 46; ISSN 1477-0520
Publisher:
Royal Society of ChemistryCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 12 works
Citation information provided by
Web of Science

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Cited By (3)

Synthesis of l -[4- 11 C]Asparagine by Ring-Opening Nucleophilic 11 C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor journal April 2018
11 C-Labeling: Intracyclic Incorporation of Carbon-11 into Heterocycles: 11 C-Labeling: Intracyclic Incorporation of Carbon-11 into Heterocycles journal October 2019
New trends and applications in cyanation isotope chemistry journal May 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
[2-¹¹C]Indole
nucleophilic [¹¹C]cyanation
Raney nickel
reductive cyclization