Ultrafast Click Chemistry with Fluorosydnones

Article abstract of DOI:10.1002/anie.201606495

We report the synthesis and reactivity of 4-fluorosydnones, a unique class of mesoionic dipoles displaying exquisite reactivity towards both copper-catalyzed and strain-promoted cycloaddition reactions with alkynes. Synthetic access to these new mesoionic compounds was granted by electrophilic fluorination of σ-sydnone Pd^IIprecursors in the presence of Selectfluor. Their reactions with terminal and cyclic alkynes were found to proceed very rapidly and selectively, affording 5-fluoro-1,4-pyrazoles with bimolecular rate constants up to 10⁴m^?1s^?1, surpassing those documented in the literature with cycloalkynes. Kinetic studies were carried out to unravel the mechanism of the reaction, and the value of 4-fluorosydnones was further highlighted by successful radiolabeling with [¹⁸F]Selectfluor.

Full text of DOI:10.1002/anie.201606495

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International Edition: DOI: 10.1002/anie.201606495
German Edition: DOI: 10.1002/ange.201606495
Click Chemistry
Hot Paper
Ultrafast Click Chemistry with Fluorosydnones
Hui Liu, Davide Audisio, Lucie Plougastel, Elodie Decuypere, David-Alexandre Buisson,
Oleksandr Koniev, Sergii Kolodych, Alain Wagner, Mourad Elhabiri, Anna Krzyczmonik,
Sarita Forsback, Olof Solin, Vꢀronique Gouverneur, and Frꢀdꢀric Taran*
Abstract: We report the synthesis and reactivity of 4-fluoro-
sydnones, a unique class of mesoionic dipoles displaying
exquisite reactivity towards both copper-catalyzed and strain-
promoted cycloaddition reactions with alkynes. Synthetic
access to these new mesoionic compounds was granted by
electrophilic fluorination of s-sydnone PdII precursors in the
presence of Selectfluor. Their reactions with terminal and cyclic
alkynes were found to proceed very rapidly and selectively,
affording 5-fluoro-1,4-pyrazoles with bimolecular rate con-
stants up to 104 mÀ1 sÀ1, surpassing those documented in the
literature with cycloalkynes. Kinetic studies were carried out to
unravel the mechanism of the reaction, and the value of
4-fluorosydnones was further highlighted by successful radio-
labeling with [18F]Selectfluor.
in vivo ligation applications.[2] Nitrones,[3] tetrazines,[4] and
diazo groups[5] are also suitable dipole partners for strained
cycloalkynes, but with the exception of tetrazines (k values up
to 103 mÀ1 sÀ1),[6] strain-promoted cycloadditions involving
cycloalkyne partners display lower second-order rate con-
stants, which typically range from 10À2 to 30mÀ1 sÀ1. Recently,
our group has identified sydnones as a new class of dipoles for
Cu-catalyzed cycloaddition with terminal alkynes, leading to
1,4-pyrazoles with complete control over regioselectivity; the
reaction was coined CuSAC (copper-catalyzed sydnone–
alkyne cycloaddition).[7] The copper-free version of this
reaction was reported by the group of J. W. Chin[8] and by
J. M. Murphy and co-workers.[9] In their work, sydnones were
found to react more slowly than azides with cyclic alkynes,
thereby limiting applicability as a bioorthogonal ligation
substrate. At the same time, we reported[10] that the presence
of a halogen in the 4-position has a beneficial impact on the
rate of the reaction, with the order of reactivity correlating
with halogen electronegativity (Cl > Br> I). In the best case,
4-chlorosydnones were ten times more reactive than azides
when reacted with bicyclo[6.1.0]nonyne (BCN, k values up to
1.6mÀ1 sÀ1),[10] and were found to be competent substrates for
terminal alkynes under Cu catalysis.[11] With these data in
mind, we aimed to develop a novel class of sydnones with the
most electronegative element, fluorine, in the 4-position. We
anticipated that these sydnones might serve as superior
substrates for bioorthogonal ligation; moreover, the cyclo-
addition of 4-fluorosydnones with terminal alkynes would
provide a new synthetic route to 5-fluoro-1,4-pyrazoles of
medicinal and agrochemical relevance. Herein, we report the
synthesis of 4-fluorosydnones, their ability to afford a large
collection of 5-fluoro-1,4-pyrazoles, and their exceptional
properties in the context of bioorthogonal chemistry
(Scheme 1).
C
lick chemistry and bioorthogonal reactions are exquisitely
suited for tracking biomolecules in their native environment,
and are therefore central to advance our understanding of
complex biological processes. As a result, tremendous efforts
have been deployed by the scientific community to enlarge
the arsenal of available bioorthogonal reactions that meet the
stringent requirements of rate, selectivity, and biocompatibil-
ity.[1] The copper-catalyzed (CuAAC) and strain-promoted
(SPAAC) azide–alkyne cycloaddition reactions are possibly
the most commonly used click reactions for in vitro as well as
[*] Dr. H. Liu, Dr. D. Audisio, L. Plougastel, E. Decuypere, D.-A. Buisson,
Dr. F. Taran
Service de Chimie Bio-organique et Marquage (SCBM)
IBITECS, CEA, Universitꢀ Paris-Saclay
91191 Gif-sur-Yvette (France)
E-mail: frederic.taran@cea.fr
Dr. O. Koniev, Dr. S. Kolodych
Syndivia SAS
Although several reports have described the synthesis and
use of 4-chloro-, 4-bromo-, and 4-iodosydnones,[12] no data are
available concerning the preparation of 4-fluorosydnones.
Preliminary studies focused on the direct electrophilic
fluorination of 4-H-sydnones but this process proved unsuc-
cessful.[13] The demonstration that aryl–fluorine bond forma-
tion can be induced by reductive elimination from high-valent
PdIV complexes[14] led us to consider this strategy as a possible
route towards 4-fluorosydnones. This approach requires the
formation of stable sydnone palladium complexes 2 with a
650 Boulevard Gonthier O’Andernach, 67400 Illkirch (France)
Dr. A. Wagner
Laboratory of Functional Chemo-Systems UMR 7199 CNRS-UdS
67401 Illkirch (France)
Dr. M. Elhabiri
Laboratory of Bioorganic and Medicinal Chemistry
UMR 7509 CNRS, ECPM
25, rue Becquerel, 67200 Strasbourg (France)
A. Krzyczmonik, Dr. S. Forsback, Prof. O. Solin
Turku PET Centre and Department of Chemistry
University of Turku, 20520 Turku (Finland)
À
C Pd s bond. Inspired by this work, we synthesized com-
Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
plexes 2a and 2b by reaction of 4-bromo- and 4-iodo-sydnone
1a and 1b with zerovalent Pd(dba)2 and triphenylphosphine
at room temperature.[15] In addition, the new bipyridine
s-sydnonyl Pd complexes 2c–2g were obtained upon gentle
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606495.
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4-fluorosydnone 3a proved challenging. Perfect chemo- and
regioselectivity led exclusively to 5-fluoro-1,4-pyrazole 4a,
which was isolated in 69% overall yield from 2d; no traces of
5-iodo-1,4-pyrazole or other side products were detected
(Scheme 3).
Scheme 3. Preparation of fluoropyrazole 4a from Pd complex 2d.
BPDS=bathophenanthroline disulfonate, Na.asc.=sodium ascorbate.
Scheme 1. Fluorosydnones as coupling partners for ultrafast click
reactions with alkynes. a) CuSAC reactions for the synthesis of
fluoropyrazoles. b) Reaction rates reported for cycloadditions with
cycloalkynes. All rate constants are second order (mÀ1 sÀ1).
Encouraged by this result, a series of Pd complexes were
prepared from both electron-rich and electron-poor 3-aryl-4-
iodosydnones.[13] These sydnone PdII precursors were sub-
jected to the two-step fluorination–CuSAC procedure de-
scribed in Scheme 3. The results demonstrate the generality of
the method; the procedure showed high functional-group
tolerance, and the reactions proceeded in less than 15 min
(Scheme 4). 5-Fluoro-1,4-pyrazoles are important synthetic
Scheme 2. Synthesis of sydnone palladium complexes 2. dba=diben-
zylideneacetone.
heating at 608C in THF (Scheme 2). All PdII complexes were
isolated and fully characterized.[13]
The Pd complexes 2a–2g were then subjected to electro-
philic fluorination. After extensive optimization,[13] Select-
fluor was identified as the sole reagent capable of affording
the desired 4-fluorosydnone 3a. As anticipated, the efficiency
of the fluorination process was found to be highly dependent
on the structural features of the Pd complex. The phosphine
complexes 2a and 2b did not react (see the Supporting
Information, Table S1, entries 1 and 2), but selected bipyr-
idine Pd complexes underwent successful fluorination to give
3a (Table S1, entries 4, 5, 8, 11, and 12). Upon reductive
elimination, the putatively formed high-valent PdIVF species
À
derived from 2c led exclusively to C Br bond formation; in
À
contrast, C F bond formation was observed in preference to
Scheme 4. Scope of the two-step reaction leading to 5-fluoro-1,4-
pyrazoles.
À
C I bond formation when 2d and 2e were subjected to
fluorination (Table S1, entries 4 and 5). Complex 2d, which
features a methoxy-substituted bipyridine ligand, was the best
À
substrate in terms of both yield and selectivity for C F bond
targets and building blocks for pharmaceutical research and
drug development,[16] but their synthesis remains challenging
and suffers from significant limitations, such as low scope, low
yields, and lack of control over regioselectivity.[17] Our
approach represents a general and efficient route to these
fluorinated heterocycles.
formation. The optimized reaction conditions thus entail
reacting 2d with 2 equiv of Selectfluor in CH3CN at 808C for
3 min.
We carried out the CuSAC with the crude reaction
mixture as the separation of 4-iodosydnone 1b and
2
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Having established that 4-fluorosydnones are responsive
steps with opposite absorption amplitudes were clearly
to click chemistry under Cu catalysis, we were tantalized by
the prospect of developing a copper-free variant with strained
cycloalkynes for potential applications in bioorthogonal
chemistry. Preliminary experiments were highly encouraging;
fluorination of 2d with Selectfluor followed by rapid filtration
and treatment with 1.5 equiv of BCN (10 mm) in a MeOH/
H2O mixture afforded the fluorinated cycloadduct 5e in
quantitative yield after a few seconds at room temperature.
We evaluated the rate constant of the reaction by HPLC
monitoring and compared the kinetic data with those
obtained for other halogenated sydnones. The results con-
firmed the dramatic increase in the reaction rate upon
introduction of the fluorine atom in the 4-position of the
sydnone core (Scheme 5).
observed in the second time range.[13] The BCN concentration
was varied, and the apparent rate constants were calculated.
The pseudo-first-order rate constants kobs1 (sÀ1) of the first
step linearly vary with [BCN]tot, suggesting that this step
corresponds to the [3+2] cycloaddition event, which leads to
a kinetic intermediate whose absorption at 280 nm experi-
ences a hypochromic shift (loss of conjugation). The second
step (hyperchromic shift at 280 nm with the restoring of the
conjugation) was found to be independent of [BCN]tot, which
is in line with a retro-Diels–Alder (rDA) step concomitant
with CO2 extrusion. The bimolecular rate constant of the
[3+2] cycloaddition (k[3+2]) and the monomolecular rate
constant of the rDA (krDA) step were calculated (Figure 1b).
The time-dependent distribution diagrams of the species
shown in Figure 1c contrast with the behavior of non-
fluorinated sydnones, where the [3+2] cycloaddition step is
likely to be rate-limiting.[9] In this case, the presence of the
fluorine substituent facilitates the [3+2] cycloaddition, which
becomes faster than the rDA step. The bimolecular rate
constant k[3+2] for the reaction of 3a with BCN was measured
to be 42 Æ 4mÀ1 sÀ1, which indicates that 4-fluorosydnone 3a is
> 1000 times more reactive than its non-fluorinated analogue
and > 300 times more reactive than azides. The use of more
strained DBCO led to a significant rate enhancement
particularly towards the [3+2] step (900 Æ 300mÀ1 sÀ1) and,
to a lesser extent, towards the rDA step. As expected, with the
highly strained seven-member-ring sulfur-containing cyclo-
alkyne TMTH,[18] both the [3+2] (1500mÀ1 sÀ1) and the rDA
(0.98 sÀ1) steps were accelerated. In line with our previous
observations,[10] electron-withdrawing groups on the aryl unit
of the sydnone partner (CF3 for 3c, F for 3b, CH3 for 3a)
increased the reactivity further, affecting the [3+2] step only;
Scheme 5. Halogen effect on the strain-promoted alkyne–sydnone
cycloaddition reaction. All rate constants are second order (mÀ1 sÀ1).
It quickly became apparent that the rate of the reaction of
4-fluorosydnone 3a with BCN was too high to be accurately
measured by HPLC. We therefore investigated the kinetic
profile of this reaction with stopped-flow techniques. The
cycloaddition was monitored by absorption detection at
280 nm under pseudo-first-order conditions. Notably, two
Figure 1. Kinetic studies. Experiments were carried out at 258C in PBS buffer containing 30% DMSO, sydnone (50 mm), and cycloalkyne (0.5–
5 mm). a) Structures of the cycloalkynes used in this study and the reaction under investigation. b) Calculated rate constants. c) Time-dependent
distribution diagrams of relevant compounds for [sydnone]=50 mm and [cycloalkyne]=0.5 mm. DBCO=dibenzocyclooctyne, TMTH=tetrame-
thylthiacycloheptyne.
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a sequential increase in k[3+2] from 1500mÀ1 sÀ1 (3a) to
Acknowledgements
3500mÀ1 sÀ1 (3b) and 12000mÀ1 sÀ1 (3c) was observed, while
krDA remained constant (ca. 0.9–1.0 sÀ1). Fluorosydnone 3c
thus reacts with TMTH with a rate constant greater than
104 mÀ1 sÀ1, which represents, to the best of our knowledge, the
fastest reaction involving a strained cycloalkyne.
V.G. held the Blaise Pascal Chair, co-founded by the French
government and the region ꢀle de France and managed by the
Ecole Normale Supꢁrieure. This work was supported by the
French Research National Agency (ANR-14-CE06-0004), the
Academy of Finland (266891), and the EC (FP7-PEOPLE-
2012-ITN-RADIOMI-316882 to A.K.). We thank Dr Mat-
thew Tredwell (University of Oxford) for helpful discussions
and Cꢁline Puente and Elodie Marcon for analytical support.
Strain-promoted click reactions offer the opportunity for
18F radiolabeling and have encouraged the development of
a range of click radiochemical reactions with azides and
tetrazines for 18F incorporation into peptides and other
biomolecules.[19] Encouraged by these results, we next
explored the use of 4-fluorosydnones as a prosthetic group
for 18F incorporation. The radiosynthesis of [18F]-3a was
successfully carried out by direct 18F fluorination of 2d with
[18F]Selectfluor bis(triflate), a reagent prepared according to
our previously described protocol.[20] Gratifyingly, the addi-
Keywords: click chemistry · electrophilic fluorination ·
fluorine-18 · kinetics · radiolabeling
tion of
a freshly prepared solution of electrophilic
[18F]Selectfluor bis(triflate) to PdII complex 2d led to the
formation of [18F]-3a in 7.5 Æ 1.7% radiochemical yield
(RCY). The crude mixture was added to BCN and stirred at
room temperature. Clean and complete conversion into the
desired cycloadduct [18F]-5e was observed after 5 min
(Scheme 6).[13] This proof of concept highlights the possibility
of using 4-fluorosydnone as a novel prosthetic group for the
preparation of 18F radiotracers.
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In conclusion, this study has provided a wealth of
information on the reactivity of a new class of mesoionic
dipoles, 4-fluorosydnones. These dipoles are within reach by
À
C F bond-forming reductive elimination from bipyridine-
ligated PdII complexes and Selectfluor. Fluorosydnones are
exceptionally reactive dipoles that are converted into a range
of 5-fluoro-1,4-pyrazoles upon cycloaddition with alkynes
under Cu catalysis. These reactions benefit from total control
over regioselectivity, offering a useful synthetic route to
fluorine-containing heterocycles that are of importance in
medicinal and agrochemical chemistry. One striking feature
of 4-fluorosydnones is their ability to undergo cycloaddition
with strained cycloalkynes with reaction rates surpassing
those documented in the literature for these dipolarophiles.
Kinetic studies enabled the determination of the rate
constants for the two individual, sequential steps of this
reaction (cycloaddition, retro-Diels–Alder reaction). Finally,
we have established that 18F-labeled fluorosydnones are
emerging as potential prosthetics for the 18F labeling of
(bio)molecules under remarkably mild reaction conditions.
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Received: July 10, 2016
Published online: && &&, &&&&
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Communications
Click Chemistry
H. Liu, D. Audisio, L. Plougastel,
E. Decuypere, D.-A. Buisson, O. Koniev,
S. Kolodych, A. Wagner, M. Elhabiri,
A. Krzyczmonik, S. Forsback, O. Solin,
V. Gouverneur, F. Taran*
&&&& — &&&&
Fast and fluorious: Fluorosydnones are
extremely reactive towards copper-cata-
lyzed cycloaddition reactions with termi-
nal alkynes and copper-free reactions with
cycloalkynes. These highly reactive click-
able reagents were prepared by electro-
philic fluorination of sydnone PdII pre-
cursors in the presence of Selectfluor.
Ultrafast Click Chemistry with
Fluorosydnones
6
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