Sydnone–alkyne cycloaddition: applications in synthesis and bioconjugation

Elodie Decuypère , Lucie Plougastel , Davide Audisio and Frédéric Taran *
Service de Chimie Bio-organique et Marquage DRF-JOLIOT-SCBM, CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France. E-mail: frederic.taran@cea.fr

Received 15th August 2017 , Accepted 15th September 2017

First published on 29th September 2017


Sydnones are among the most popular mesoionic compounds studied so far for cycloaddition reactions. However, despite their good chemical stability and versatility, only a limited number of research groups have worked on their chemistry and use in organic synthesis. This feature article aims at providing an overview of the most recent developments in sydnone–alkyne cycloadditions, with particular attention on the strategies that allow us to achieving high regiocontrol and milder reaction conditions. The recent discovery that this dipole is able to undergo click and biorthogonal reactions with cycloalkynes may stimulate renewed interest from the scientific community. Given the high potential and flexibility of this family of mesoionics, we believe that major developments are to be expected both in terms of organic synthetic methodologies and biorthogonal chemistry applications in the field of chemical biology.


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Frédéric Taran (left), Lucie Plougastel (second to the left), Elodie Decuypère (second to the right), Davide Audisio (right)

Frédéric Taran (left) is a group Leader in the department of chemistry at the French Alternative Energies and Atomic Energy Commission (CEA) located at Saclay. Dr Taran secured a PhD in chemistry at the Paris XI University under the supervision of Dr Charles Mioskowski. In 1996, he moved to a post-doctoral position with Prof. Sir Derek Barton at Texas A&M University (USA) and then came back to CEA in 1998 as a permanent researcher. His research aims at developing new reagents for bioorthogonal chemistry to address important problems in the fields of bioconjugation, labelling, imaging and drug delivery.

Lucie Plougastel (second to the left) completed a PhD in chemistry at the French Alternative Energies and Atomic Energy Commission (CEA) under the supervision of Dr Frédéric Taran. Her work focused on the development of the strain-promoted cycloaddition between sydnones and cycloalkynes. She obtained her PhD in 2016 and is now working in a French Health Agency on the regulation of chemicals.

Elodie Decuypère (second to the right) is a postdoctoral fellow at ETH, Zürich. She obtained her PhD in chemistry at the University of Paris-Saclay under the supervision of Dr Frédéric Taran in 2016. She worked on the development of new (3+2) cycloadditions involving mesoionic compounds and alkynes under copper catalysis. Her current research focuses on the synthesis of new oligonucleotide gapmer–polyamine conjugates to improve their potency.

Audisio Davide (right) holds a PhD degree in medicinal chemistry from the University of Paris Sud (France, Dr M. Alami and Dr S. Messaoudi). After postdoctoral experience working on asymmetric catalysis at the Max-Planck-Institut für Kohlenforschung (Germany, Prof. N. Maulide), in 2012 he joined the chemistry department of Eli Lilly & Co (UK). Since 2014, he has been a permanent researcher at CEA, the Alternative Energies and Atomic Energy Commission (France), in the research group of Dr Frédéric Taran. His research interests span diverse areas within organic chemistry, including carbon radiolabelling methodologies and the development of new tools for bio-orthogonal chemistry.


1 Introduction

More than 60 years ago a major contribution to the field of heterocyclic chemistry was made by the pioneering work of R. Huisgen on 1,3-dipolar cycloadditions.1 Azide–alkyne cycloaddition, often referred to as the Huisgen reaction, has certainly been the most popular, due to the development of the copper-catalyzed version by B. M. Sharpless and M. Meldal and its remarkable impact in the field of click chemistry.2,3 R. Huisgen also identified several mesoionic compounds that react with dipolarophiles to form various heterocycles, but these transformations have been largely neglected until recently.

The term mesoionic, derived from the contraction of “mesomeric” and “ionic”, is utilized to describe 5-membered ring heterocycles with the particularity of comprising two opposite charges.4 A variety of canonical structures for each mesoionic compound can be found, involving the delocalization of 6 π-electrons, and therefore the delocalization of the positive and negative charges among the ring. However, it is impossible to find a non-charged representation of these compounds. Among mesoionics, sydnones are certainly those that have attracted the most attention. Indeed, sydnones possess the advantage of being highly stable and easily synthesized, which is not the case for all mesoionic compounds. Despite the remarkable advances in modern organic chemistry, synthetic access to sydnones still relies on the original procedure reported in 1935 by Earl and Mackney.5 A two-step approach, consisting of nitrosylation of an amino acid derivative, generally performed using sodium nitrite under aqueous acidic conditions, followed by a cyclo-dehydration step in the presence of acetic or trifluoroacetic anhydride (Scheme 1).


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Scheme 1 General synthesis for the preparation of sydnones.

Among the eight possible dipolar resonance forms of sydnones, the most common representation found in the literature is the one in which the negative charge is carried by the exocyclic oxygen atom leading to an enolate-type structure and the positive charge is located on the substituted nitrogen atom (Scheme 2, I). However, this structure is not representative of the real charge distribution in the mesoionic ring. Since their discovery in 1935 and the review by Baker and Ollis published in 1957,6 numerous studies, sometimes contradictory, dealing with the electronic and physical properties of the structure of sydnones have been published.7 The earlier molecular calculations performed in the 50s and 60s asserted that the negative charge was essentially localized on the exocyclic oxygen, with the carbon–oxygen bond having little carbonyl character.8 These original studies explain the traditional representation of sydnones we use today (Scheme 2, I), but since the emergence of new and more reliable analytic techniques, these studies have been disputed.9 Thus, the stretching frequency of the C–O bond, being about 1730 cm−1 is in agreement with a carbonyl-type bond. This suggestion of an exocyclic C[double bond, length as m-dash]O double bond is also confirmed by the bond length (1.197 Å) calculated from the IR spectra of sydnones and by single crystal X-ray analysis. The values obtained with these analyses also suggest that sydnones might not be aromatic systems as it was presented originally.


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Scheme 2 Resonance structures of sydnones.

These results are consistent with the observed reactivity of sydnones in 1,3-dipolar cycloaddition with acetylenes,10 behaving as cyclic azomethine imines (representations II and III depicted in Scheme 2). After cycloaddition, the bicyclic intermediate evolves into the corresponding pyrazole via the extrusion of carbon dioxide through a retro Diels–Alder process as shown in Scheme 3.


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Scheme 3 Thermal cycloaddition between sydnones and alkynes published by Huisgen in 1962.

Back in the 50s, the interest in the sydnone motif was entirely focused on their biological properties, such as antibacterial, antineoplastic and anti-inflammatory activities.11 However, because of the increasing interest in heterocyclic chemistry, the cycloaddition between sydnones and alkynes has gained attention over time. Indeed, the pyrazole motif is a privileged structure in biologically active molecules and the sydnone–alkyne reaction represents straightforward access to this important scaffold. In his original publication, R. Huisgen proved that sydnone–alkyne reaction was compatible with a variety of monosubstituted alkynes as well as with disubstituted alkynes bearing alcohol, acetal, acyl and ester groups. Nevertheless, this reaction suffered from poor regioselectivity when an unsymmetrical alkyne was used and required high temperatures.12 Since this first report, a number of studies have been carried out in order to understand and improve the regiocontrol of this cycloaddition and it has finally been shown that the nature of the alkyne could impact dramatically the regioselectivity of this reaction.

In recent years, a surprising amount of attention has been given to this exotic family of heterocycles. Efforts from several research groups have established novel ways to control the regioselectivity of the transformation, propelling such cycloaddition to become a hot spot once again. In addition, their exquisite reactivity with strained cycloalkynes under biologically relevant conditions highlighted sydnones as a new functionality in the click chemistry toolbox.

We believe that this transformation might become a major tool for the preparation of highly functionalized pyrazoles and a good alternative to the use of the azide–alkyne cycloaddition in the field of bioorthogonal chemistry. This feature article aims to highlight the renewed interest in the sydnone–alkyne cycloaddition and describes its applications in organic synthesis and bioconjugation.

2 Thermal cycloadditions

Since the pioneering report by R. Huisgen and co-workers in 1962 describing the thermal 1,3-dipolar cycloaddition between sydnone dipoles and alkynes as a dipolarophile, it clearly appeared that two major limitations might have hampered the subsequent developments of this fascinating transformation: harsh conditions and poor regiocontrol.10 High temperatures (up to 180 °C) over extended time periods were usually required in order to carry out the reaction: an important limitation for sensitive substrates. In addition, in the presence of nonsymmetrical alkynes, the two possible pyrazole products were obtained with poor or no regioselectivity.

In 1973, Houk's group provided the first explanation for the low degree of selectivity observed in the sydnone–alkyne cycloaddition.13 In their efforts to understand the origin of reactivity and regioselectivity in 1,3-dipolar cycloaddition using frontier molecular orbital theory, this group observed that the presence of the electron-withdrawing carbonyl group in this peculiar class of azomethine imine dipoles has a pronounced effect in lowering the energy of the LUMO orbital of sydnones. In addition, calculations indicated that the terminal orbital coefficients of the dipole system are almost identical to that in the LUMO. Thus, although LUMO control of the reactivity was observed, a decrease in the regioselectivity of sydnone cycloadditions with respect to those observed with simpler azomethine imines was expected.14

Since this seminal work, a number of efforts have been made to optimize this cycloaddition. Initial studies have focused on softening the reaction conditions. With this aim, polarized alkynes, such as propiolate esters, have been utilized to lower the temperature of cycloaddition, nevertheless no significant enhancement in the regioselectivity was observed (Scheme 4).14–17


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Scheme 4 Low selectivity thermal sydnone–alkyne cycloadditions.

With the aim to overcome such limitations, a variety of synthetic strategies were investigated. The use of highly sterically hindered diphenylmethyl propiolate for example allowed exclusive formation of 1,3,5-trisubstituted pyrazoles in high yields (Scheme 5a).18 In 2007, González-Nogal's group showed that the use of alkynylsilanes is particularly suitable for sydnone cycloadditions and allows a spectacular level of regiocontrol (Scheme 5b).19 The use of activated alkynyl phenyl sulphones (Scheme 5c) was also successful.20


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Scheme 5 Alkynes that enable high control of the regioselectivity of the transformation.

One of the most notable example of selective thermal cycloadditions with sydnones has been described by J. Harrity's group using alkynylboronates as dipolarophiles.21,22a,b It was found that a large variety of sydnones were compatible with alkynylboronates, granting unprecedented synthetic access to pyrazole boronic esters, a valuable platform for further metal catalyzed functionalizations.

In the case of 4-unsubstituted sydnones (Scheme 6a, R = H), the use of a terminal alkyne (R′ = H) provided the corresponding pyrazoles with good levels of regiocontrol in favor of the 3-boronate. Impressively, switching to a phenyl substituted alkyne provided the opposite regioisomer with complete control over the selectivity. When 4-substituted sydnones were used, exquisite levels of regiocontrol were observed in all cases examined.


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Scheme 6 Regioselective thermal cycloadditions with sydnones and alkynylboronates.

To understand these experimental observations, DFT calculations were carried out and the transition states of the [3+2] cycloaddition step of the transformations were computed. The origin of the reversal of regioselectivity was explained using steric factors, which appear to contribute largely. Another significant experimental finding was the higher reactivity of sydnones bearing an electron withdrawing p-nitrophenyl group on the electropositive nitrogen (without loss of the regioselectivity). The computed transition states were significantly less demanding in energy (both ΔH and ΔG compared to N-phenylsydnones) and the presence of the nitro substituent increased the electrophilicity index of the sydnone, meanwhile reducing the energy value of the corresponding sydnone/LUMO orbital. These indications suggest a type III LUMO controlled dipole cycloaddition reacting through an inverse-electron-demand mechanism, in good agreement with the previous findings by Houk's group.13b

Very recently, J. Harrity's group reported the first example of sydnone cycloaddition, with internal unsymmetrical alkynes, proceeding under ambient conditions (Scheme 6b).22c 4-Pyridylsydnones were shown to react with alkynyl trifluoroborate derivatives and a Lewis acid to yield the corresponding dialkynylboranes with complete control over the regioselectivity. The effects of the directing group in position C4 were explored and the desired pyrazole borane products were further functionalized enabling access to a variety of fully substituted pyrazoles.

Practical applications of the thermal cycloaddition have been described in the literature. In 2016, a collaborative effort by J. Harrity's group has reported an efficient method to access analogs of combretastatins, a major class of tubulin-binding agents.23 Sydnones were utilized as convenient and versatile building blocks to provide an original library of analogues of combretastatin A, bearing different substitutions on the pyrazole moiety. Rationally driven regioselective cycloadditions with sydnones enabled the authors to use the pyrazole heterocycle as a platform to connect substituents with almost complete control over selectivity. It is worth mentioning that high temperatures and long reaction times have not been a limitation for the formation of the desired products, which could be isolated in good yields. This elegant methodology allowed access to 1,5-disubstituted, 4,5-disubstituted and 3,4-disubstituted pyrazole analogs of combretastatin A with nanomolar activities (Scheme 7).


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Scheme 7 Synthetic access to potent combretastatin-A analogs.

Another remarkable example of thermal sydnone–alkyne cycloaddition was reported in 2016 for the preparation of a new class of high performance thermoset polymers (Scheme 8).24 The authors employed bifunctional sydnones with trifunctional alkyne derivatives as an innovative platform for fully aromatic thermosets based on pyrazole cross-linking units. High thermal and mechanical performances, functional group stability and final material properties under standard processing conditions, illustrated the usefulness of this original approach.


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Scheme 8 Synthesis of new pyrazole based thermoset materials.

3 Copper-promoted sydnone–alkyne cycloadditions

3.1 Cu(I) catalyzed cycloadditions

As previously mentioned, thermal alkyne sydnone cycloadditions are often biased by the lack of regioselectivity and harsh conditions required in order to achieve full conversion and high yields. A step forward to solve this longstanding issue has been made by our group, which serendipitously discovered a milder version of this transformation during a high throughput screening project aimed at finding novel chemoselective and biocompatible reactions.25 It was found that the use of catalytic amounts of Cu(I) allowed the reaction conditions to be softened (with temperatures below 60 °C compatible for the first time) and, perhaps more interestingly, complete control over the selectivity in favor of the 1,4-disubstitued pyrazole. The substrate scope was equally shown to be functional group tolerant and remarkably broad (Scheme 9).
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Scheme 9 Cu catalyzed sydnone–alkyne cycloaddition (CuSAC) substrate scope. BPDS: bathophenanthroline disulfonate, Na Asc.: sodium ascorbate.

Although this Cu catalyzed sydnone–alkyne cycloaddition (CuSAC) reaction still presents some limitations (N-alkyl sydnones are not competent substrates), it has many advantageous features. The reaction proceeded smoothly in many solvents, including biological media such as pure human blood plasma at 37 °C, giving clean reactions with no trace of by-products (Scheme 10).


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Scheme 10 Use of CuSAC in aqueous and biological media.

In order to explore the potential of this transformation in the field of bioconjugation, it was envisioned to label a BSA–sydnone conjugate, obtained by a standard peptide coupling reaction, with a dansylated alkyne (Scheme 11). Under CuSAC aqueous conditions, 74% of sydnones linked to BSA were successfully converted into pyrazoles, according to MALDI-TOF analysis. In addition, sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS–PAGE) analysis confirmed the effectiveness of the conjugation.25


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Scheme 11 Application of CuSAC to protein labeling.

In a subsequent study aiming to avoid the manipulation of the highly toxic N-nitroso intermediate, a key precursor in the synthesis of sydnone (Scheme 12), our group developed a one-pot version of this transformation. With this improved protocol, the desired pyrazoles could be isolated from the corresponding glycine derivatives, with in situ formation of sydnones.26 This procedure was fast, efficient and regioselective, and allowed us to obtain 1,4-disubstituted pyrazoles directly from the corresponding glycines. Though this protocol cannot be utilized for labeling biological entities, it is synthetically useful for the construction of such pharmaceutically relevant heterocycles.


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Scheme 12 One-pot synthesis of pyrazoles from glycine derivatives.

It could be argued that a main limitation of CuSAC is the sole access to 1,4-disusbtituted pyrazoles. To address this issue, our group has studied the influence of substitution at the C4 position of the sydnone on the reactivity.27 It was observed that this position has a major effect on the transformation, both in terms of efficiency and selectivity. As described in Table 1, the presence of sp2 and sp3 substituents was not tolerated under standard CuSAC conditions. Interestingly, the presence of halogens, with the exemption of iodine, allowed full conversion of the starting material with moderate to good selectivity in favor of 1,4,5-trisubstituted pyrazoles (Table 1, entries h, i and j).

Table 1 Influence of C4 substitution of the sydnone on CuSAC reaction

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Entry R Yield of 18a (%) 18/19
a Isolated yield.
a H 98 100/0
b Me 7 100/0
c Ph None
d CF3 None
e CN 10 50/50
f CHO None
g I Traces
h Br 74 83/17
i Cl 80 96/04
j F 86 100/0


In the case of 4-bromo and 4-chloro sydnones, it was found that a second product, 1,3,5-trisubstituted pyrazoles, was formed during the reaction as a minor isomer. Despite the moderate regioselectivity, the case of the generation of the bromide is very interesting, because it offers a useful handle for potential functionalization of the pyrazole by metal-catalyzed coupling reactions. Optimization of reaction conditions, identified diimidazoquinoxalines as a privilege family of ligands for this transformation enabling the formation of the desired 1,4,5-trisubstituted pyrazoles with high yields and complete regioselectivity (Scheme 13).27 The presence of bromide could be further exploited by adding a third substitution on the pyrazole by performing a Suzuki reaction. This reaction tolerated aromatic as well as aliphatic boronic acid.


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Scheme 13 CuSAC with bromosydnones and subsequent Suzuki functionalization.

The case of 4-fluorosydnones (Table 1, entry j) was appealing both in terms of direct synthetic access to 5-fluoropyrazoles as well as a fascinating perspective in 18F-radio-labeling chemistry. Surprisingly, no report on 4-fluorosydnone was described in the literature and in our hands the use of traditional electrophilic fluorination protocols failed to give the desired product. Inspired by the work of T. Ritter and M. Sanford,28 we developed a procedure based on electrophilic fluorination of sydnone–Pd(II) precursors with Selectfluor allowing the isolation of the desired 4-fluorosydnones in a very fast and clean reaction. This strategy involves a selective reductive elimination step from the putatively formed high-valent Pd(IV)F intermediate. After screening, the methoxy-substituted bipyridine Pd-complex was found to be the best substrate both in terms of yield and selectivity favoring C–F bond formation over the C–I bond. The subsequent CuSAC reaction afforded 5-fluoropyrazoles as pure products (Scheme 14).29


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Scheme 14 Synthetic access to 5-fluoropyrazole enabled by CuSAC.

Literature reports describing the synthesis of 5-fluoro-1,4-pyrazoles are rare because of limitations such as low efficiency and lack of regioselectivity.30 The CuSAC approach provides a versatile and direct route to these fluorinated heterocycles, which are important motifs for pharmaceutical research and drug development.31

3.2 Cu(II) promoted cycloadditions

In 2015, J. Harrity's group reported a divergent sydnone–alkyne cycloaddition using a stochiometric amount of copper(II) salts.32 Based on the previous evidence suggesting that the sydnone–alkyne cycloaddition proceeds through an inverse-electron-demand cycloaddition–cycloreversion mechanism,22 the author speculated that the Lewis acid activation of the mesoionic compounds might have a positive impact on the reactivity by decreasing the energy of the sydnone/LUMO and increasing its electrophilicity. A variety of Lewis acids were screened to evaluate their influence on the reaction and it was found that only copper(II) salts display a significant enhancement in the speed of the reaction by reducing the reaction time significantly. The best results were obtained with Cu(OTf)2 and Cu(OAc)2 leading respectively to the formation of opposite isomers: 1,3- and 1,4-disubstituted pyrazoles (Scheme 15).
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Scheme 15 Selective copper(II) promoted sydnone–alkyne cycloaddition.

The regioisomer obtained using Cu(OTf)2 was the same as the background (Scheme 15), but the reaction time could be reduced in some cases to only 20 minutes (in place of 24 hours). DFT calculations along with IR analysis confirmed the positive effect of the Lewis acid coordination on the exocyclic oxygen in decreasing the activation energies of the transition states of the cycloaddition. In the case of Cu(OAc)2, the major regioisomer generated was the same as for the CuSAC reaction developed by our group, suggesting an analogue mechanistic pathway. The authors experimentally found that a Glaser coupling occurred during the transformation and Cu(OAc)2 was reduced in situ to generate Cu(I) acetylide species leading to the opposite outcome in terms of selectivity. In addition, computational results confirmed that the lower Lewis acid character of Cu(OAc)2 disfavors its complexation to the sydnone, while the transition state with Cu(I) acetylide shows a tight copper nitrogen interaction responsible for the lowering of the activation barrier.

With the aim to optimize the performance of the Cu(OAc)2 promoted cycloaddition, J. Harrity and F. Rutjes described in 2016 a continuous flow synthesis of pyrazoles (Scheme 16).33 Silica supports were functionalized to incorporate amino groups, which were used to assist the copper coordination. The silica supported catalyst performed well and the loading of copper promoter required to achieve full conversion could be reduced to 25–30%. In addition, a single equivalent of the alkyne was now sufficient for transformation, suggesting an alternative mechanism to the Glaser homo-coupling for the in situ reduction of Cu(II) to Cu(I), such as disproportionation taking place at a temperature above 120 °C. This new procedure was then implemented in a flow system and allowed the reactions to be carried out under milder conditions, for shorter times and gave access to 1,4-disubstituted pyrazoles in scalable amounts.


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Scheme 16 Cu-Catalyzed pyrazole synthesis in continuous flow.

4 Ring strain cycloadditions between sydnones and alkynes

As described above, the sydnone–alkyne 1,3-dipolar cycloaddition either requires the use of high temperatures or a metal catalyst in order to activate the alkyne. An alternative strategy is the activation of the alkyne via ring strain, as demonstrated in 1961 by Wittig and Krebs34 and more recently in 2004 by Bertozzi's group35 in the presence of an azide dipole.

4.1 Sydnones–arynes cycloadditions

Arynes are extremely reactive organic compounds which are easily prepared from properly designed aromatic precursors usually via the elimination of two ortho-substituents.36 These compounds are known to react even at low temperatures in different types of transformations among which are the pericyclic reactions. They have demonstrated excellent reactivity in 1,3-dipolar cycloadditions leading to a variety of heterocycles in good yields and under mild conditions. Already in his original publication in 1962, Huisgen mentioned the first [3+2] cycloaddition involving a sydnone with an aryne.10a The detailed work was subsequently reported at the end of the 1960s.37 2-Phenylindazole was obtained in 49% yield after the treatment of 3-phenylsydnone with benzyne obtained from benzenediazolium-2-carboxylate (Scheme 17a). In 1976, Kato extended this cycloaddition to several other mesoionics and the best results were observed when sydnones were used as dipoles, and good yields were obtained even when the C4 position was substituted (Scheme 17b).38
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Scheme 17 First examples of sydnone–benzyne cycloaddition to obtain indazoles.

In the past few decades, indazole has become a privileged structure in heterocyclic chemistry since it displays a large variety of biological activities.39 Until now, efforts have been mostly focused on the synthesis of 1H-indazoles and numerous methods have been described to access these structures. In contrast, the preparation of 2H-indazoles has attracted less attention even if these structures possess diverse bioactivities. This can be explained by their difficult preparation and the limitations in the existing methodologies. In 2010 and 2011, the groups of R. Larock and F. Shi published an extensive study on the 1,3-dipolar cycloaddition of sydnones and benzyne derivatives in order to obtain a series of substituted 2H-indazoles in good to excellent yields, under mild conditions and in a straightforward manner.40,41 Under optimized conditions, benzyne derivatives were obtained from the corresponding silylaryl triflates upon treatment with TBAF and the reaction was performed in THF at room temperature (Scheme 18).


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Scheme 18 Sydnone–aryne cycloaddition, by Larock and Shi.

In their publications, they also demonstrated the good compatibility of this reaction with a wide variety of sydnones and aryne precursors. Among the sydnones studied, only those bearing an electron withdrawing group or a sp3 carbon at the C4 position were found to be respectively unreactive or sensible under the reaction conditions, whereas it can be noted that the reaction was tolerant in the presence of a halogen at this position. Variation of the aryl or alkyl substituent in the N3 position proved to have no negative impact, except that when N-(4-nitrophenyl)sydnone was used for the reaction, in this case only traces of product could be obtained. As for the aryne precursors, nine symmetrical or unsymmetrical silylaryl triflates were studied and excellent yields were obtained in each case, except for a 2,3-pyridine precursor, where no conversion was observed. Interestingly, when an unsymmetrical aryne precursor, both sterically or electronically biased, was used for the study, no regiocontrol was observed. This is in agreement with the molecular orbital calculations performed by K. Houk in 1973 suggesting that N2 and C4 have similar orbital coefficients, rendering nucleophilic attack of the alkyne on the sydnone equally probable on both positions.13 The 2H-indazoles thus obtained could be further substituted by Pd-catalyzed couplings when C4-halogeno sydnones are used as starting materials making this reaction favorable for the synthesis of highly substituted bioactive compounds.

In 2016, N. Garg's group described the synthesis of the strained 4,5-benzofuranyne and its trapping with a variety of nucleophiles and cycloaddition partners (Scheme 19a).42 Also in this case, the reactivity with N-phenylsydnone displayed a low degree of selectivity (ratio 1.3[thin space (1/6-em)]:[thin space (1/6-em)]1) when compared to other dipoles. An interesting application of sydnone/aryne cycloaddition to the synthesis of the PARP inhibitor Niraparib, was described earlier this year by Y. Li's group (Scheme 17b).43 In this study the authors reported the novel generation of substituted arynes via Grob fragmentation of a bicyclic precursor. Also, herein, the reaction with N-substituted sydnone was not regioselective (ratio 1[thin space (1/6-em)]:[thin space (1/6-em)]1.2). Nevertheless, the minor isomer could be isolated and further functionalized into the desired bioactive molecule.


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Scheme 19 Examples of non-selective sydnone/aryne cycloadditions.

Two remarkable examples of regioselective sydnone/aryne cycloadditions have been recently reported by T. Ikawa's and S. Akai's group (Scheme 20).44,45 The use of silyl substituents at the ortho-position to the aryne plays a major role in controlling the reaction to favor the formation of a less sterically hindered product (ratios > 85[thin space (1/6-em)]:[thin space (1/6-em)]15). Unfortunately, the sole p-methoxyphenyl 4-substituted N-phenyl sydnone was utilized as a substrate in both cases and it is not possible to evaluate if the selectivity is substrate dependent or a more general feature of this peculiar class of arynes.


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Scheme 20 Silyl group controlled benzyne cycloaddition with 3,4-disubstituted sydnone.

4.2 Cycloaddition reactions of sydnones with cyclohexynes and cyclopentynes

Compared to benzynes, cyclohexynes and cyclopentynes have attracted much less interest in synthetic chemistry. This can be explained by their challenging synthesis and extremely high reactivity. The cyclohexynes were first highlighted by Roberts in 195746 and the cyclopentynes by Wittig in 1960;47 since then both compounds have mostly been used in Diels–Alder cycloadditions. Recently, the groups of N. Garg and K. Houk extended the applications of these strained alkynes to the synthesis of new heterocyclic compounds.48 Both cyclohexynes and cyclopentynes were generated using the corresponding silyl triflate derivatives treated with CsF. In this study, the authors investigated a series of dipoles, including phenylsydnone, which have been reacted with a cyclohexyne compound. The reaction with the sydnone was found to be efficient, affording the resulting pyrazole product in 82% yield (Scheme 21a). As for the cyclopentyne, the pyrazole resulting from the reaction with the sydnone was obtained in 59% yield (Scheme 21b).
image file: c7cc06405e-s21.tif
Scheme 21 Cycloaddition reactions of sydnones with strained alkynes. The reaction of phenylsydnone with: (a) cyclohexyne, (b) cyclopentyne, (c) 3,4-piperidyne and (d) 3,4-oxacyclohexyne.

In 2015 and 2016, the same groups expanded the study of the strained alkynes by generating a 3,4-piperidyne49 and different oxygen-containing cyclic alkynes.48 When 3,4-piperidyne was reacted with various nucleophiles and unsymmetrical dipole partners, a clear regioselectivity was interestingly observed towards the products derived from nucleophilic attack on the para-position, this being explained in the publication by a distortion/interaction model. This model suggests that cyclic alkynes are unsymmetrically distorted in their ground state and that the nucleophilic attack occurs at the terminus of the alkyne that is more distorted. This regioselectivity was in contrast not observed when a sydnone was used for the reaction; in this case a ratio of 1.3[thin space (1/6-em)]:[thin space (1/6-em)]1 was obtained (Scheme 21c). The same observation was made when the authors reported the synthesis of the intermediate 3,4-oxacyclohexynes and their subsequent reaction with various trapping agents. A low regioselectivity was observed when the sydnone was used in this reaction compared to what could be observed for the other unsymmetrical cycloaddition partners and nucleophiles (Scheme 21d).50

4.3 Strain-promoted sydnone–alkyne cycloaddition (SPSAC)

In the early 1960s, Wittig and Krebs observed that the cyclooctynes, the smallest stable cycles containing a triple bond, reacted very efficiently with phenyl azide by producing only one product, the triazole.51 This reaction was described by Wittig as being extremely fast at ambient temperature and sometimes even leading to explosions. This particular reactivity of cyclooctynes is due to the tension resulting from the distortion of the angles of the alkyne (158° instead of 180°). From Wittig's observations, in the early 2000s Bertozzi's group used this reactivity for bioconjugation applications and developed Strain-Promoted Azide–Alkyne Cycloaddition (SPAAC), a copper-free version of the well-known copper-catalysed azide–alkyne cycloaddition (CuAAC).52 Avoiding the use of the cytotoxic copper catalyst, SPAAC extended further the application of 1,3 dipolar azide–alkyne cycloaddition in living systems.

In analogy to the work of Bertozzi, in 2014 Chin's group published the first example of Strain-Promoted Sydnone–Alkyne Cycloaddition (SPSAC) by reacting N-phenylsydnone with the cyclooctyne BCN (Scheme 22a).53 An equimolar amount of the reagents was mixed in methanol at room temperature resulting in the formation of the corresponding pyrazole in 99% yield. The reaction appeared to be clean and took place in only 30 minutes at 160 mM concentration. The biocompatibility of this reaction was shown by the site-specific incorporation of a non-naturally occurring amino acid, functionalized by the BCN, to the recombinant GFP protein which was further labeled by a sydnone functionalized with a BODIPY motif (Scheme 22b).


image file: c7cc06405e-s22.tif
Scheme 22 (a) Reaction of phenylsydnone with BCN. (b) Genetic encoding of BCN in protein sfGFP and labelling using the SPSAC reaction.

In recent years, the discovery and exploration of bioorthogonal reactions has become a major challenge. Such reactions must be inert with regard to the myriad of functionalities present in biological media, leading to the formation of stable covalent bonds between two bio-inert groups, small in size and ideally non-toxic (for applications in living cells and in living organisms). These reactions must also be carried out at physiological pH and temperature. Finally, one of the major criteria for biorthogonal reactions is the speed of the reaction. Transformations should possess a high rate constant when performed in aqueous media so that the resulting product is obtained rapidly even when the reaction is carried out at very low concentrations of reagents. The rate constants of common bioorthogonal reactions range from 10−5 to 105 M−1 s−1.54

As for the cycloaddition involving phenylsydnone and BCN reported by Chin, the rate constant was determined to be 0.054 M−1 s−1 in MeOH/H2O 55[thin space (1/6-em)]:[thin space (1/6-em)]45.53 This rate constant is smaller than the one of the SPAAC (0.14 M−1 s−1 with BCN)55 and of the other major biorthogonal reactions such as the inverse electron-demand Diels–Alder reactions between tetrazines and strained alkenes and alkynes. In parallel to the report from Chin, our group published in 2014 a kinetic study with various substituted sydnones with the objective to increase the speed of the SPSAC reaction.56 A library of sydnones was screened and the influence of substitutions (on positions N3 or C4) of the mesoionic on the speed of the strain-promoted reaction was evaluated. The second-order rate constants were performed in a mixture of PBS buffer/DMSO 9[thin space (1/6-em)]:[thin space (1/6-em)]1 at 25 °C. The results are summarized in Scheme 23.


image file: c7cc06405e-s23.tif
Scheme 23 Influence of the sydnone substituents on the speed of the SPSAC.

A strong influence of the nature of the substitution on the nitrogen atom N3 was observed. N-Alkyl sydnones were not competent substrates with BCN under the reaction conditions. In contrast, N-aryl sydnones carrying an electron-withdrawing group on the aromatic ring accelerated the rate of the reaction, this increase being moreover correlated with the electronegativity of the substituent.

As for the substitutions on the C4 position, the insertion of a C–C bond had little impact on the rate of the reaction. The presence of a withdrawing group leads to a decrease in the speed while a donor group has a positive impact on the rate constant. Interestingly, the presence of halogens provided the most remarkable effect on the rate constants; this effect was correlated to the electronegativity of the halogen atom.

In this study, 4-chlorinated sydnones were found to be the most reactive with the rate constant being 30 times higher than the one for N-phenylsydnone. The combined effect of the presence of a chlorine atom in the C4 position and an electron-withdrawing group on the aryl on the N3 position lead to a sydnone which react 60 times faster than the N-phenylsydnone (Scheme 24).


image file: c7cc06405e-s24.tif
Scheme 24 Rate constants of phenylsydnone and chlorinated sydnones when reacted with BCN (1.5 eq.) in PBS pH 7.4 (100 mM)/DMSO 9[thin space (1/6-em)]:[thin space (1/6-em)]1 at 25 °C.

This high reactivity of chlorinated sydnones was applied to the fluorescent labelling of a model protein, bovine serum albumin (BSA). A chlorinated sydnone was first covalently bound to the BSA and the resulting bioconjugate was then subjected to cycloaddition reaction with a BCN functionalized with the rhodamine fluorophore TAMRA (Scheme 23). The results obtained by SDS–PAGE and MALDI-TOF indicated that more than 90% of the 4-chlorosydnones on BSA were transformed into pyrazoles in less than 5 min of reaction. This experiment demonstrated the applicability of this reaction for bioorthogonal protein labelling and introduced the SPSAC as a potentially new biorthogonal reaction for bioconjugation applications (Scheme 25).


image file: c7cc06405e-s25.tif
Scheme 25 Fluorescent labelling of bovine serum albumin using the SPSAC reaction with 4-chlorosydnones.

An alternative strategy to improve the kinetics of this cycloaddition is to increase the strain on the cyclic alkyne. In 2016, K. Houk's and J. Murphy's group performed DFT calculations in order to investigate the potential reactivity of various strained cycloalkynes and cycloalkenes versus the N-phenyl sydnone.57 Two dibenzocyclooctyne derivatives, DIBAC and BARAC were found, both theoretically and experimentally, to be highly reactive towards sydnone cycloaddition. A rate constant of 1.46 M−1 s−1 was obtained with BARAC (in MeCN[thin space (1/6-em)]:[thin space (1/6-em)]H2O 1[thin space (1/6-em)]:[thin space (1/6-em)]1) whereas the rate constant of the reaction with DIBAC was determined to be 0.902 M−1 s−1 (in MeOH[thin space (1/6-em)]:[thin space (1/6-em)]H2O 55[thin space (1/6-em)]:[thin space (1/6-em)]45, Scheme 26). The increase in the reaction rate can be explained by the smaller bond angle observed in the cyclooctynes DIBAC and BARAC compared to BCN. Thus, the dibenzocyclooctynes are more pre-distorted and less energy is needed to reach the transition state of the cycloaddition.


image file: c7cc06405e-s26.tif
Scheme 26 Reactivity of N-phenyl sydnone with DIBAC and BARAC.

Based on calculations, the authors demonstrated that norbornene was dramatically less reactive with sydnones than with tetrazine and identified two mutually orthogonal pairs, sydnone–DIBAC and tetrazine–norbornene. This exquisite cross-reactivity was applied to the fluorescent labelling of two model proteins (BSA and OVA) functionalized respectively with DIBAC and norbornene (Scheme 27). This demonstrated the possibility to chemically modify two distinct biomolecules at the same time and therefore opened new possibilities in simultaneous monitoring of multiple processes in the biological environment.


image file: c7cc06405e-s27.tif
Scheme 27 Orthogonality between sydnone–DIBAC and norbornene–tetrazine reactions.

Following our previous results on 4-halogeno-sydnone, our group envisioned the synthesis of 4-fluorosydnones for their potential application in SPSAC.29 These fluorinated mesoionics proved to be extremely reactive towards cyclooctynes. Kinetic measurements were performed under pseudo-first order conditions at 25 °C in phosphate buffer (PBS) containing 30% DMSO using stopped-flow techniques. The presence of the fluoro-substituent at position 4 induced a spectacular increase in the rate of reaction. Thus, the rate constant with BCN was determined to be 42 ± 4 M−1 s−1, more than 1000 times faster than N-phenylsydnone. Moreover, when the cyclooctyne DIBAC and the more strained alkyne TMTH were used for the reaction, the rate constants of respectively 900 ± 300 M−1 s−1 and 1500 ± 300 M−1 s−1 were obtained. The reaction between TMTH and 4-fluorosydnone is nowadays the fastest reaction involving a strained alkyne ever described.

Interestingly, the stopped-flow technique enabled the two reaction steps of the SPSAC, that is to say the [3+2]-cycloaddition and the retro Diels–Alder reaction rDA (Table 2), to be visualized separately.

Table 2 Kinetic studies. Experiments were carried out at 25 °C in PBS buffer containing 30% DMSO, [sydnone] = 50 μM, [cycloalkyne] = 0.5–5 mM

image file: c7cc06405e-u2.tif

Alkyne k [3+2] k rDA
a M−1 s−1. b s−1.
image file: c7cc06405e-u3.tif 42 ± 4 0.02 ± 0.01
image file: c7cc06405e-u4.tif 900 ± 300 0.06 ± 0.01
image file: c7cc06405e-u5.tif 1500 ± 300 0.98 ± 0.06


Ultra-fast click reactions offer the possibility to manage difficult reactions even at very low concentrations. This property was further exploited in proof-of-principle experiments for positron emission tomography (PET) applications. This medical imaging technique, being mostly based on the use of the short-life radioisotope fluorine-18, requires rapid techniques in order to incorporate the isotope into complex bio-molecules. As a proof of concept, the radiosynthesis of [18F]-fluorosydnone was successfully performed starting from a pallado-sydnone precursor and using [18F]-Selectfluor bis(triflate) as a source of electrophilic fluorine-18. The radioactive compound was obtained in 7.5 ± 1.7% radiochemical yield. In a second step, the mixture was added to BCN in order to lead in 5 minutes to the expected [18F]-pyrazole cycloadduct. This model reaction proved that [18F]-fluorosydnone represents a potential clickable tool for the insertion of fluorine-18 in complex biomolecules (Scheme 28).


image file: c7cc06405e-s28.tif
Scheme 28 Synthesis of [18F]-sydnone and its cycloaddition reaction with BCN.

5 Conclusions

Since their discovery in 1935, mesoionic sydnones have undergone exciting and challenging developments. Initially known for their biological properties, their inherent reactivity was unveiled by the remarkable work of Huisgen almost thirty years later in 1962. Harsh reaction conditions along with poor control over the regioselectivity have slowed down the investigations related to this remarkable example of cycloaddition. Over the last decade, new exciting discoveries have propelled this exotic class of azomethine imines to a broader interest in the chemical community. Three major strategies have been used to highlight the usefulness of this reaction. The use of peculiar alkynes, such as for example alkynylboronates, allowed us to controlling in a selective manner the outcome of the transformation and further functionalize the pyrazole scaffold. The discovery of copper-catalyzed sydnone–alkyne cycloaddition (CuSAC) was another major advancement in the field and allowed for the first time to envisioning the application of this reaction in click chemistry and bioconjugation. Finally, their utilization with strained cycloalkynes has recently established sydnones, in their own right, as a unique tool for bio-orthogonal chemistry. The size of sydnones is quite bigger than azides which can be a drawback on comparing CuSAC or SPSAC to their equivalent CuAAC and SPAAC; however the possibility to tune the reactivity of sydnones by appropriate substitutions is a major advantage. This possibility has been successfully exploited to develop ultra-fast reactions, a prerequisite for in vivo applications.

We witnessed a number of groundbreaking advancements, but new strategies should be investigated in order to push further the limits of sydnone–alkyne cycloadditions. One major challenge is the lack of regiocontrol in the presence of unsymmetric arynes: endeavors to overcome this limitation will certainly be highly appreciated. We believe that we are still at the outset and new exciting developments will follow for this peculiar family of mesoionics.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The CEA (French Alternative Energies and Atomic Energy Commission), ANR (French National Agency of Research) and the European community are acknowledged for their financial support. We are grateful to the following research associates for their invaluable contribution: S. Kolodych, E. Rasolofonjatovo, S. Specklin, H. Liu, S. Gabillet; and to M. Riomet and S. Bernard for proofreading.

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Footnote

These authors contributed equally to this work.

This journal is © The Royal Society of Chemistry 2017