Rapid Protium–Deuterium Exchange of 4-Aminopyridines in Neutral D2O under Microwave Irradiation

Abstract

Article (Accepted Version) http://sro.sussex.ac.uk Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Abstract: 4-Aminopyridines undergo surprisingly rapid and highly-selective H/D exchange at C-2 and C-6 in neutral D2O upon microwave irradiation at only 190 °C for 2 h in a sealed vessel. This method contrasts and complements acid-mediated H/D exchange, requires no catalyst and is appropriate for the synthesis of deuterium isotopologues of N-and C-substituted 4-aminopyridines and a benzofused (quinoline) analogue.

Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by 15N Hyperpolarized Nuclear Magnetic Resonance

“…Thus, DMAP-d 2 was synthesized via H/D exchange from DMAP in D 2 O under microwave irradiation as reported in the literature. 89 Examination of a sample containing [IrCl(COD)(IMes)] (5 mM), DMAP-d 2 (6 equiv), and Na 15 NO 2 (25 equiv) in methanol-d 4 and exposure to 3 bar p-H 2 at a polarization transfer at −3.5 mG led to a signal gain of 13,811 after investigation at 9.4 T (4.56% 15 N polarization level). The corresponding value with 1 H-DMAP was 12,036, and hence introducing the 2 H is beneficial to SABRE.…”

“…As stated, deuteration of ligands within the active catalyst can be beneficial. ,,,, We postulated that deuteration of the ortho protons in D , to give DMAP- d 2 , may lead to further improvements in 15 N polarization. Thus, DMAP- d 2 was synthesized via H/D exchange from DMAP in D 2 O under microwave irradiation as reported in the literature . Examination of a sample containing [IrCl­(COD)­(IMes)] (5 mM), DMAP- d 2 (6 equiv), and Na 15 NO 2 (25 equiv) in methanol- d 4 and exposure to 3 bar p -H 2 at a polarization transfer at −3.5 mG led to a signal gain of 13,811 after investigation at 9.4 T (4.56% 15 N polarization level).…”

NHC‐Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines

“…Junk described complete exchange (99 %D) for the synthesis of [D 7 ]aniline in D 2 O/NaOD at 400 8C (600 bar) over 10 h. [24] Recently Bagley reported an unselective deuteration of aniline and aminopyridines in neutral D 2 O at 190 8C (high pressure, 16 bar) with up to 25 %D of isotopic enrichment for all C(sp 2 ) À H aniline positions. [25] Unfortunately, all these methods are difficult to transfer to tritium chemistry, yielding mainly low specific activity [26] or are incompatible with some functional groups due to the harsh conditions used. Another approach reported by Garnett starting from nitrobenzene reacting over Raney nickel (alternatively platinum or palladium) with D 2 or D 2 O (or T 2 or HTO respectively) at a temperature lower than 75 8C over days allows the corresponding deuterated/tritiated anilines to be obtained in low %D or %T unless a very large excess of isotope source is used.…”

Metabolic Stability of the Demyelination Positron Emission Tomography Tracer [18F]3-Fluoro-4-Aminopyridine and Identification of Its Metabolites

“…Attempts to fluorinate 4AP-d 6 with reactive electrophilic fluorination reagent SelectFluor in water or a combined water/chloroform solvent system at 80 °C did not generate deuterated 3F4AP in useful yields (<5% conversion), prompting us to explore the direct protium/deuterium exchange of 3F4AP. We decided to test H/D exchange under microwave irradiation as it requires lower temperature and shorter reaction time compared to other methods (Bagley et al 2016;Esaki et al 2006;Werstiuk et al 1989). As shown in Figure 4, reaction of 3F4AP in D 2 O under microwave irradiation at 170 °C gave 2,6-d 2 -3F4AP with D incorporation of 98% at C-2 and 48% at C-6 after 12 hours.…”