10.1002/ejoc.201800554
European Journal of Organic Chemistry
COMMUNICATION
The formamide as an unconventional amine protecting group for
PET radiochemistry
Jimmy Erik Jakobsson,[a] Gaute Grønnevik,[ab] Waqas Rafique,[a] Karoline Hartvig[a] and Patrick
Johannes Riss*[abc]
Abstract: We developed a versatile, rapid and robust high yielding
radiochemistry adapted protocol utilising formamides as masking
groups for secondary and tertiary amines. Selective reducing
conditions were devised using borane reagents. In this protocol
formamide functionalities were found to have an orthogonal reactivity
to most other carbonyl functions, while effectively protecting amines
from oxidative degradation. We exemplify the newly developed
methodology by synthesising a µ-opioid PET radiotracer and a
dopamine PET radiotracer analogue.
masked as carbamates, however, tertiary amines cannot. In
another example, synthesis of hypervalent iodanes as
precursors, free amines are frequently oxidised and the
available strategy for avoiding oxidation, protonation via strong
acids only works occasionally and is incompatible with sensitive
functional groups. Hypervalent iodane nucleofuges are the only
transition metal free methodology that consistently provides
radiofluorination of both deactivated and sterically hindered
positions in good yields.[3]
We believe that developing a protective group approach adapted
to radiochemistry will improve the predictability and usefulness
of iodonium ylides as versatile radiofluorination precursors for
accessing complex substrates, as well as benefit transition metal
catalysed radiochemistry.
Introduction
Molecular imaging is a powerful non-invasive tool that can
visualise biological pathways inside living organisms. An
example of molecular imaging is positron emission tomography
(PET[1]) which is used for both diagnosing various disease states
e.g. cancer and Alzheimer’s disease and for unravelling
biological mechanisms in vivo. PET imaging is based on
positron emitting isotopes. Most often, the positron emitting
nuclide of choice is fluorine-18 due to its excellent decay
characteristics and convenient half-life (109.7 min). Fluorine-18
is produced in a cyclotron via the 18O(p,n)18F nuclear reaction
and obtained as 18F- in an aqueous solution. The fluoride is
typically retained on an anion exchange cartridge, reformulated
with a phase transfer catalyst and azeotropically dried to
enhance the nucleophilicity. Production of radiotracers for
clinical use require rigorous quality controls, therefore it is of
uttermost importance to limit the use of potentially toxic reagents
as far as possible to minimise the number of chemicals that
needs to be tested for to ease clinical translation.
Results and Discussion
We surmised that masking amines as formamides would
extinguish their nucleophilicity, allow synthesis of primary,
secondary or tertiary amines and remove sensitivity to oxidation,
thus providing
a
versatile strategy. Functional group
interconversions such as hydrolysis or reduction further amplify
the scope of products. Radiofluorination of all non-activated
substrates was achieved from the corresponding iodonium ylide
precursor in excellent conversion (87±10%, n=114, radioTLC)
with high reproducibility in between both, individual runs and
batches under standard radiofluorination conditions[3a] and
without radioactive side products.
Scheme 1 Radiofluorination performed using ylide (4.0 mg, 10 µmol), crypt-
222 (10 mg, 27 µmol) K2CO3 x 1.5 H2O (1.84 mg, 11 µmol) and 18F- (400 MBq)
in DMF (1 ml) at 130 °C for 20 min. Crypt-222 = 4,7,13,16,21,24-Hexaoxa-
1,10-diazabicyclo[8.8.8]hexacosane
There is a strong demand for new radiotracers and
consequently new means of incorporating fluorine-18 into both
aromatic and aliphatic systems are needed. Significant effort has
been made to develop new labelling methodologies,[2] however,
little attention has been given to increase the functional group
tolerance of said methods in order to allow for radiosynthesis of
final products in one step. The most abundant fluorinated motif
in drug compounds are aryl fluorides, while activated systems
are readily radiofluorinated via a nitro-to-fluoro substitution
reaction, deactivated substrates require other types of
precursors often in combination with a transition metal catalyst
2b]
selected from Cu, Ni or Pd.[2a,
However, the conditions
developed for the purpose proceed in significantly lower yield or
not at all in presence of free amines[2b, 2f, 2g](ESI). This makes
necessary the use of protective groups during labelling followed
by deprotection. Primary and secondary amines can readily be
A standard workup included dilution of the reaction mixture with
water and purification using a Chromabond HR-P C18 cartridge
to remove residual precursor and DMF left from the
radiofluorination reaction (78±3% recovered radiotracer in ~95%
RCP, n=3, radioTLC). Use of other solvents produces
regioisomeric mixtures and reduced yield.
First we focussed on devising reduction conditions to convert
formamide model compounds into tertiary amines. Prior to
amide reduction, residual water has to be removed, cartridges
packed with various drying agents and azeotropic distillation was
evaluated as alternatives (Table 1).
[a]
Realomics Strategic Research Initiative, Department of Chemistry,
Faculty for Mathematics and Natural Sciences, University of Oslo,
Norway. E-mail: Patrick.riss@kjemi.uio.no
[b]
[c]
Norwegian Medical Cyclotron AS, Nydalen, Oslo, Norway
Department of Surgery and Neuroscience, OUS-Rikshospitalet HF,
Oslo, Norway
This article is protected by copyright. All rights reserved.
Jakobsson, Jimmy Erik
