10.1002/ejoc.201801457
European Journal of Organic Chemistry
COMMUNICATION
18
Convenient Entry to F-labeled Amines Through the Staudinger
Reduction
E. Johanna L. Stéen#[a, b], Vladimir Shalgunov#[a], Christoph Denk[c], Hannes Mikula[c], Andreas Kjær[b,d]
Jesper L. Kristensen[a] and Matthias M. Herth*[a, b]
,
Abstract:
Fluorine-18
possesses
outstanding
decay
characteristics for positron emission tomography (PET) imaging.
Therefore, it is ideally suited for clinical applications. As such,
improved strategies to incorporate fluorine-18 into bioactive
molecules are of utmost importance. Indirect 18F-labeling with
amino-functionalized synthons displays
a convenient and
versatile approach to synthesize a broad variety of PET tracers.
Herein, we report a method to convert 18F-labeled azides to
primary amines by means of the Staudinger reduction. Aliphatic
and aromatic 18F-labeled azides were converted to the
corresponding amines with high conversion yields. The method
could easily be automated. From a broader perspective, the
applied strategy results in two useful synthons from a single
precursor and thus increases the flexibility to label diverse
chemical scaffolds with minimal synthetic effort.
Figure 1. Comparison of radiosynthetic methods to access 18F-labeled
amines from azides. PPh2PhSO3Na: Sodium
diphenylphosphinobenzene-3-sulfonate
Introduction
suitable for direct 18F-nucleophilic substitution approaches.[3]
Positron emission tomography (PET) is a powerful and non-
invasive nuclear imaging technique, which makes use of
radiolabeled molecules (PET tracers) at tracer levels to study
biochemical processes.[1] PET is routinely used in the clinic for
diagnosis and staging of diseases, as well as for treatment
monitoring.[2] The technique has also found widespread use in
Over the years, a number of synthons have been developed and
among these structures, 18F-labeled amines display an interesting
platform for indirect labeling.[3] For example, they can be applied
in the formation of amide, sulfonamide, urea and carbamate
motifs, as well as in reductive alkylations and Michael additions.
Up to date, various methods have been published to synthesize
18F-labeled aliphatic and aromatic amines [3,4]. Synthons such as
4-[18F]fluoroaniline and 4-[18F]fluorobenzylamine can be obtained
via aromatic fluorination of an electron-deficient precursor and
subsequent reduction [4]. The syntheses of aliphatic amines like
2-[18F]fluoroethylamine ([18F]2) are usually based on a two-step
fluorination-and-deprotection strategy. [5] As a rule, the first 18F-
labeled intermediate in such strategies cannot be directly used for
an indirect labeling approach. In 2012, Glaser et al. reported a
novel synthetic approach, which was based on a Cu-mediated
reduction of 2-[18F]fluoroethylazide ([18F]1, Figure 1) [6]. This
method has the advantage that two radiolabeled synthons, an
azide and an amine, are synthesized within one reaction
sequence (Figure 2). Multiple pathways for indirect 18F-labeling
can be tested while starting from a single precursor. This reduces
synthetic effort and adds flexibility to the tracer development
process, especially when a library of structurally related 18F-
labeled compounds has to be evaluated.
drug
development
to
study
pharmacokinetics
and
pharmacodynamics.[1a-b] Fluorine-18 (18F) is the most frequently
applied radionuclide for PET in the clinic. Its decay characteristics
result in excellent image resolution, acceptable radiation burden
and the half-life of 110 min is convenient for clinical investigations
and commercial distributions.[3] Consequently, several strategies
have been developed to efficiently incorporate fluorine-18 into
bioactive molecules.[3] Indirect labeling strategies applying small
18F-labeled synthons, which can easily be attached to target
molecules, are of special relevance for structures that are not
[a]
E. J. L. Stéen, V. Shalgunov, J.L. Kristensen, M. M. Herth
Department of Drug Design and Pharmacology
University of Copenhagen
Universitetsparken 2, DK-2100 Copenhagen, Denmark
# These authors contributed equally
* Corresponding Author. E-mail: Matthias.herth@sund.ku.dk
E. J. L. Stéen, A. Kjær, M. M. Herth
Department of Clinical Physiology, Nuclear Medicine and PET
University Hospital Copenhagen, Rigshospitalet,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark
C. Denk, H. Mikula
Institute of Applied Synthetic Chemistry
Technische Universität Wien
Getreidemarkt 9, AT-1060 Vienna, Austria.
A. Kjær
[b]
[c]
[d]
Our aim with the present study was to explore methods beyond
the Cu-mediated reduction of azides to access amines.
Especially, we aimed to substitute Cu with an organic reducing
agent that would allow for performing the reduction in
homogenous solution, which in turn would facilitate automation of
the procedure (Figure 1). The Staudinger reduction is reported to
rapidly reduce azides to amines in organic chemistry.[7]
Cluster for Molecular Imaging
Department of Biomedical Sciences, University of Copenhagen,
Blegdamsvej 3, 2200 Copenhagen, Denmark.
Supporting information for this article is given via a link at the end of
the document.
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