Merging hypervalent iodine and sulfoximine chemistry: a new electrophilic trifluoromethylation reagent
Electrophilic trifluoromethylation is at the forefront of methodologies available for the installation of the CF 3 moiety to organic molecules; research in this field is largely spurred by the availability of stable and accessible trifluoromethylation reagents, of which hypervalent iodine and sulfoximine based compounds have emerged as two prominent reagent classes. Herein, we describe the facile synthesis of an electrophilic trifluoromethylation reagent which merges these two scaffolds in a novel hypervalent iodosulfoximine compound. This presents the first analogue of the well-known Togni reagents which neither compromises stability or reactivity. The electronic and physical properties of this new compound were fully explored by X-ray crystallography, cyclic voltammetry, TGA/DSC and DFT analysis. This solution stable, crystalline reagent was found to be competent in the electrophilic trifluoromethylation of a variety of nucleophiles as well as a source of the trifluoromethyl radical. Furthermore, the possibility of enantioinductive transformations could be probed with the isolation of the first enantiopure hypervalent iodine compound bearing a CF 3 group, thus this new reagent scaffold offers the opportunity of structurally diversifying the reagent towards asymmetric synthesis.
Introduction<!>Reagent design and synthesis<!>Tautomerization of chlorinated 5<!>Structure and properties<!>Reactivity studies<!>Conclusions<!>Conflicts of interest
<p>The unique properties imbued by the triuoromethyl group to organic molecules has made this motif ubiquitous in compounds of interest in pharmaceutical, agrochemical and materials research. 1 Its introduction oen leads to changes in the chemical, biological and physical properties of a given compound; for example, lipophilicity and membrane permeability of drug candidates are improved. Furthermore, the energetic cost of breaking the C-F bond compared to other Cheteroatom bonds means that uorinated compounds display enhanced chemical stability. The accessibility of this group is largely dependent on the development of CF 3 transfer reagents, which can be classied according to their nucleophilic, electrophilic or radical character. The utility of nucleophilic triuoromethylation reagents, exemplied by triuoromethyltrimethylsilane (TMSCF 3 ), has been expansively studied, however the need for differential functional group tolerance has spurred extensive research in the development of electrophilic triuoromethylation reagents. 2 One prominent class of electrophilic triuoromethylating reagents are hypervalent iodine compounds 1 and 2 (Fig. 1), rst reported by one of our groups in 2006. 3 Reagents 1 and 2, have been used to transform a wide variety of nucleophiles, for the generation of new C-, N-, O-, P-, or S-CF 3 bonds. In many cases this process corresponds to a substitution of a hydrogen atom by the CF 3 group. Synthetically and commercially, reagents 1 and 2 are readily accessible as crystalline shelf-stable compounds, resulting in vigorous research efforts by one of our groups and others towards utilizing them in disparate applications. This research has received particular attention, given the increasing interest of the synthetic community for new methodologies in organouorine chemistry. The activation of 1 and 2 can be achieved using Brønsted or Lewis acids which increases their electrophilic or iodonium-like character, thus matching the electrophilic character of the reagent to the nucleophile. 3c,4 One of our groups recently reported the activation of reagent 2 with TiCl 4 which enabled the triuoromethylation of sulfonate salts, a transformation which is otherwise difficult to achieve. 4b Another class of electrophilic uoroalkylating reagents are sulfoximine based compounds of type 3 (Fig. 1). 5 They have been successfully employed for the introduction of triuoro-and monouoromethyl groups by Shibata and coworkers, 6 diuoromethyl by the groups of Hu 7 as well as Olah and Prakash, 8 and for bromodiuoro-and dichlorouoromethyl by one of our groups. 9 In 2012, Hu and coworkers greatly expanded the eld of application of peruoroalkylated sulfoximine reagents by showing that mono-and diuoromethyl derivatives can also be efficient reagents for the nucleophilic transfer of peruorinated entities. 10 More recently, Akita and coworkers have published the use of the same reagent as a source for generating diuoromethyl radicals. 11 One year later, one of our groups extended this methodology to other peruoroalkyl radicals including the triuoromethyl group. 12 One important property of these compounds is the ease with which they can be structurally diversied and their properties nely tuned for targeted applications.</p><p>Given the growing body of research in new tri-uoromethylating reagents based on compounds of the type shown in Fig. 1, we were interested in merging these two scaffolds to generate a new reagent, resulting in the design of compound 4. Vastly altering the scaffold of 1 and 2 has been investigated in our labs and others, however in most cases these modications either resulted in diminished reactivity, product instability, or proved difficult to synthetically access. 13 One such example saw the introduction of a para-NO 2 group on compound 1, which resulted in reduced solubility and instability under acidic reaction conditions. 13d In 2018 an acyclic chloro(phenyl)triuoromethyliodane reagent was reported, which showed similar reactivity to 1 and 2. 13e Previous attempts at synthesising this compound by Yagupolskii and Umemoto proved challenging, presumably due to the lack of stability of the acyclic structure. 14 The reported compound was found to be stable as a solid, but substantial degradation was observed in commonly used solvents, for example 65% decomposition in MeCN-d 3 aer 1 day. This nding suggests cyclic hypervalent iodine compounds such as 1 and 2 are more stable in solution compared to acyclic analogues. A further challenge in tri-uoromethylation chemistry that has yet to be addressed is the introduction of chirality onto the reagent scaffold, 13b in order to enable the synthesis of enantioenriched triuoromethylated substrates. Given the chirality of the sulfoximine group in 3, we anticipated that reagent 4 could be used to investigate enantioinductive transformations.</p><p>In this paper we describe the synthesis and characterization of an enantiopure, hypervalent iodosulfoximine compound 4 which is also an efficient triuoromethylating reagent. To the best of our knowledge, this is the rst example of a hypervalent iodine bonded to the nitrogen of a sulfoximine moiety incorporated into the 5-membered heterocyclic ring. The properties of compound 4 were investigated by X-ray crystallography, cyclic voltammetry, TGA/DSC and DFT. We conducted a comparative reaction screening which shows that in most cases reagent 4 reacts in a very similar fashion to reagent 1 and 2, a very gratifying nding as this is the rst successful modication of the original iodine(III) reagents which does not signicantly impact reactivity or reduce stability.</p><!><p>A sulfoximine substituent on the aromatic ring ortho to the iodine center was expected to have a strong enough electron withdrawing character to stabilize the 3-centre 4-electron hypervalent iodine bond. Hypervalent iodine compounds bearing a sulfoximine group have previously been reported by Bolm and co-workers, however the reported compounds were designed for the transfer of the sulfoximine moiety, and hence not a part of the 5-membered heterocycle. 15 Synthetic accessibility to iodine(I) reagent precursor 5 has previously been reported by the Versailles lab, starting from phenyl triuoromethyl sulfoxide 6 (Scheme 1). 16 This three-step procedure involves the preparation of a sullimine 7 (via a Ritter-like process), its subsequent oxidation and nal Ndeprotection sequence to deliver the sulfoximine 8. This protocol can be safely followed on a multi-gram scale, allowing for the preparation of 33 g of 8. 17 In the next step, the tri-uoromethylsulfoximine group acts as an ortho-directing substituent and various electrophiles can be introduced. Thus, ortho-lithiation followed by quenching with excess iodine gave the iodoarene 5 in excellent yields on a 15 g scale. 18 In a more recent report, sulfoximine 8 could be accessed via a one-pot protocol starting from commercially available phenyl triuoromethyl sulde, using phenyliodine diacetate and ammonium carbamate followed by acid hydrolysis. Application of this method gives compound 5 in two steps as opposed to three, however large scale synthesis via this route has not yet been established. 19 The improved one-pot procedure for the synthesis of reagent 1 was then successfully applied to iodosulfoximine 5 (Scheme 2), allowing for the isolation of reagent 4. 20 Oxidation is rst achieved using trichloroisocyanuric acid (TCICA) and 5 mol% triuoroacetic acid (TFA) as a Brønsted acid catalyst, 21 which facilitated the reaction at room temperature. Aer one hour, complete conversion to the chloroiodane 9 was conrmed by 19 F NMR, and a subsequent ligand exchange at the iodine atom with potassium acetate was also found to be facile at room temperature with full conversion in 30 minutes. This is in contrast to the conditions reported for the synthesis of 1, which involved heating at reux for both the oxidation and ligand exchange steps. Finally, a second ligand exchange with TMSCF 3 gave 4 in excellent yield (74%) over the three steps. Reagent 4 could be puried by recrystallization from a mixture of pentane/ MeCN/Et 2 O (see ESI for details †), a simplied protocol compared to that reported previously for 1 and 2. 20 The one-pot protocol could also be applied on a 10 g scale to give compound 4 in 75% (see ESI for details †). This yield compares well with that of the synthesis of 1, which can be obtained in 72% over three-steps from 2-iodobenzoic acid, and is improved compared to the four-step protocol for the synthesis of 2 which can be obtained in 67% yield from methyl 2-iodobenzoate. 20 Additionally, the intermediate chlorinated and acetylated iodine(III) precursors could be isolated in excellent yields, 95% for chloroiodane 9 and 90% for 10 (starting from 9) following the standard procedures (see ESI for details †). 20 Reagent 4 could be accessed from isolated compound 10, albeit with no improvement of yield compared to the one-pot protocol starting from 5. It is worth noting the presence of a triuoromethyl group linked to the sulfur atom is crucial as the same transformation with the Smethyl sulfoximine failed (see ESI, Scheme S1 †).</p><p>Given the chirality of the sulfoximine group on the reagent scaffold, we envisaged taking advantage of this property for the preparation of an enantiopure reagent. We were pleased to nd that the iodosulfoximine 5 could be separated by preparative chiral HPLC using a Chiralpak AS-H column and hexane/ isopropanol (80/20) as mobile phase on a 2 g scale. The separated enantiomers were congurationally stable on the bench as conrmed by analytical chiral HPLC aer several weeks. With the stable enantiomeric form of (+) and (À)-5 in hand we proceeded to synthesize the enantiopure form of (À) and (+)-4 respectively (see ESI for optical rotation values †). Gratifyingly, the one-pot protocol for the preparation of reagent 4 preserved the absolute conguration of the sulfur atom as conrmed by analytical chiral HPLC, which gave a single peak suggesting no epimerization had occurred. Furthermore, good quality single crystals that were used for an X-ray diffraction study of the structure of chloroiodane (À)-9 could be obtained by slow evaporation of a dichloromethane solution, thereby determining the absolute conguration to be (S)-(À)-9 (Fig. 2).</p><!><p>Interestingly, during our rst attempts at oxidizing the iodine center with TCICA using the original conditions reported for the synthesis of 1 and 2 without use of a Brønsted acid catalyst, an unexpected product was obtained. We found that conducting the reaction at room temperature with 0.34 eq. of TCICA gave a mixture of products, the desired cyclic structure 9 and another product characterized by a new peak in the 19 F NMR spectrum at À63.89 ppm in MeCN-d 3 . We assigned this new compound to an acyclic N-chlorinated structure 9 0 . Furthermore, we found that conducting the reaction at À20 C gave a mixture of 99 : 1 of 9 0 to 9, and slow irreversible transformation of 9 0 into 9 could be observed at room temperature over 12 hours. Hence, 9 0 is the kinetic product for the chlorination with TCICA, with 9 being the thermodynamically favoured tautomer (Scheme 3).</p><p>The structure of N-chlorinated compound 9 0 could be conrmed by NMR and HRMS analysis, crystal structural analysis was inaccessible as compound 9 0 tautomerizes to 9 in solution at low temperatures as well as in the solid state. To further corroborate the acyclic structure of 9 0 we compared the obtained NMR data with that of the newly synthesized and previously reported compounds (see ESI, Table S1 †). The Versailles lab has recently reported the synthesis of an Nchlorinated sulfoximine analogue of 8 via the same method, 22 and the 19 F NMR signal of this compound was reported to be at À68.19 ppm in MeCN-d 3 , which is a 4 ppm difference to that of 9 0 . Analysis of the 19 F NMR chemical shis of the synthesized cyclic reagents 4, 9 and 10 showed a 13 ppm difference between the signal of acyclic 9 0 and that of the cyclic structures (which Scheme 2 Synthesis of hypervalent iodosulfoximine reagent 4. TCICA ¼ trichloroisocyanuric acid, TFA ¼ trifluoroacetic acid. are in À77 ppm region). Additionally, to conrm this acyclic structure we examined the 13 C NMR shis for the carbon atom bound to iodine on the aromatic ring, C ipso (see ESI, Table S1 †) which gives a distinct chemical shi depending on the oxidation state of the iodine atom. In iodine(I) compounds the ipsocarbon is strongly shielded as a result of relativistic effects, which is reduced in iodine(III) and iodine(V) species. 23 This trend is observed in both cyclic and acyclic variants of oxidized iodine species and is not impacted strongly by the nature of the ligands at the iodine atom (see Table S1 in ESI †). 23 When comparing the 13 C NMR shis of the new and previously synthesized compounds we found that derivatives of iodine(I) gave a signal in the 95 ppm region, whilst iodine(III) species had a 13 C NMR chemical shi of 110-122 ppm for C ipso , a signicant difference of 15-27 ppm.</p><p>The instability of N-chloroamines and their use as oxidants in organic synthesis is well described; N-chloroamides such as TCICA and N-chlorosuccinimide are known to undergo reactions with amines via Cl + oxidation, hence it is unsurprising to nd that TCICA reacts preferentially with the imine moiety. 24 To probe the mechanism of the tautomerization process we monitored the reaction prole by 19 F NMR spectroscopy (see ESI for details †). The rate of decay of 9 0 and the rate of formation of 9 was found to be the same. Increasing the concentration or the temperature accelerates the tautomerization process, with the fastest reaction rates observed with the addition of TFA at room temperature. Furthermore, an induction period was seen at various temperatures and concentrations, with no intermediate observed and only traces (<1%) of by-products identied in the 19 F NMR spectrum. Given the sigmoidal curve for the reaction prole, which is characteristic of autocatalytic processes, we could rule out such a mechanism by addition of 10 mol% of product 9 to a mixture of 5, which was found to have the same reaction prole as the same reaction mixture without the addition of compound 9 (see ESI for details †). Since many chlorination reactions using N-haloamines have been proposed to occur via formation of radical species such as variations of the Hofmann-Löffler-Freytag reaction, 25 we explored this possibility by conducting the reaction in the absence of light, but found the reaction to proceed; EPR studies of the reaction mixture also gave no signal for radical intermediates. Kinetic studies conducted thus far have proved inconclusive. However, from these qualitative ndings we could rule out covalent isomerization processes where the Cl atom migrates from nitrogen to iodine or bimolecular transition states involving two 9 0 molecules, where Cl atom transfer occurs in a concerted fashion, as these would show rst or second order reaction proles respectively. One suggestion for the mechanism by which this occurs would be that the reaction proceeds via an ionic mechanism involving an iodonium [8-I-2] species, these intermediates have been previously reported to form via a dissociative mechanism from [10-I-3] compounds. 26 Further investigation of this unusual reaction mechanism is underway in our laboratories.</p><!><p>In order to get a full understanding of the stability and reactivity of 4, we performed several analytical measurements. TGA/DSC analysis revealed no melting event to occur before the onset of rapid thermal decomposition at 146.3 C within a short temperature window. A similar observation was made in previous reports for compound 1. 27 The solution stability of the reagent was checked in several solvents. Aer 1 day traces of decomposition products (<5%) were observed in methanol-d 4 and 15% aer 4 days, similarly 8% decomposition was observed aer 4 days in CDCl 3 , but the compound was stable in MeCN-d 3 for 1 week, and only traces (<5%) of decomposition products were observed in acetone-d 6 aer 1 week. Thus, the reagent is stable in commonly used solvents for triuoromethylation reactions for extended periods, and the minor decomposition observed is indicative of its reactivity.</p><p>Good quality single crystals of compound 4 for X-ray diffraction could be obtained by slow evaporation of a dichloromethane solution (Fig. 3). The structural features of this new reagent were compared with that of compounds 1 and 2 (Table 1). 3a,b The I1-N1 bond of compound 4 is elongated relative to the I1-O1 bond of reagent 2 (2.284(2) in 4 vs. 2.1176(14) Å in 2) and is the same as that of compound 1 (2.283(2) Å), indicating that the carboxylate and sulfoximine moieties have similar electron withdrawing properties. This trend is reversed when looking at the I1-CF 3 bond lengths, which is shortest in compound 1 (2.219 Å), with similar bond lengths observed for compounds 2 and 4 (2.267(2) and 2.250(3) Å respectively). Interestingly, the lengthening of the I1-N1 bond in the sulfoximine reagent does not coincide with a signicant shortening of the I1-CF 3 bond length which is typically Scheme 3 Oxidative chlorination of 5 with TCICA giving N-chlorinated compound 9 0 which tautomerizes to cyclic chloroiodane 9.</p><p>Fig. 3 Structure of hypervalent iodine compound 4 (see Table 1 for structural properties). H atoms are omitted for clarity; thermal ellipsoids given at 50% probability.</p><p>observed in cyclic hypervalent iodine structures of this type. The CF 3 -I1-N1 bond angle in the sulfoximine reagent (173.35(9) ) is closer to 180 , compared to the I1-C8-O1 bond angles of reagents 1 and 2 which are around 170 , a consequence of the large N1-S1 bond length (1.482(2) Å). Furthermore, structural overlap of the three compounds (Table 1) highlights the distortion of the torsion angles N1-I1-C1-C2 (4.6(2) ) and C8-I1-C1-C6 (10.1(2) ) in 4 out of plane of the phenyl group, which is not as pronounced as the corresponding angles in compound 2 (11.56(15) and 13.21(2) ), with 1 being essentially co-planar.</p><p>The structural properties of these hypervalent iodine reagents can be loosely related to their reactivity in that a lengthening of the I1-X1 bond length (usually coinciding with the shortening of the I1-CF 3 bond length) results in faster initial rates of reaction when toluene sulfonic acid is used as the model substrate, with 1 showing much faster reactivity than 2. 13b However, this correlation only loosely holds as solid-state bond lengths may not truly reect solution bond lengths due to crystal packing effects.</p><p>Given the novel structure of 4, we aimed at gaining a deeper understanding of the electronic effects of the sulfoximine moiety on the hypervalent iodine scaffold and how this may compare to the existing reagents. Molecular electrostatic potential (MEP) surfaces were generated for the visualisation of electron density on all three compounds for comparison using the previously reported methods (Fig. 4, see ESI for details †). 28 Comparing the MEP electron density of the three reagents, a strong polarization towards the ligands is observed in all three compounds, with the calculated dipole moments following the trend: 5.2 D in 1; 5.1 D in 4; and 3.0 D in 2. The electron density on the heteroatom directly bound to iodine is similar in all three compounds at around À0.05 au. Larger differences are seen in the expression of the "s-hole"a region of positive charge at the iodine atom, 28 the most strongly expressed region of positive potential is seen in compound 1 followed by that of compound 4. These electronic properties have an impact on the strength and directionality of reagent-substrate or reagent-solvent interaction, wherein a nucleophile or polar solvent would be much more strongly coordinated to compounds 1 and 4 compared to 2.</p><p>Finally, cyclic voltammetry experiments were conducted to compare the redox potentials of the new reagent 4 with that of 1 and 2 (see ESI for details †). The rst cathodic peak potential for reagent 4 vs. [FeCp 2 ]/[FeCp 2 ] + was found to be À2.02 V which is similar to that of 1 (À1.91 V vs. [FeCp 2 ]/[FeCp 2 ] + ), compound 2 was found to be the most difficult to reduce with a rst cathodic peak potential of À2.42 V under the same conditions. Hence, the cyclic voltammetry data further corroborates the similarity of compound 4 to 1, both of which are more easily reduced compared to compound 2.</p><!><p>Aer establishing the structural similarity of this new reagent 4 to the existing triuoromethylation reagents 1 and 2, we proceeded to investigate its reactivity. To this aim, we attempted the triuoromethylation of various S-, C-, O-, and P-centered nucleophiles (Scheme 4), and compared the yields to the previously reported results for 1 and 2. Triuoromethylation of sulfonic acids was investigated rst (entry 1), as this has been established as a clean and fast reference reaction in one of our labs for testing newly designed reagents. 13b To our satisfaction, we found that compound 4 performed comparatively to 1 when camphorsulfonic acid 11 is used as a substrate, giving 92% 19 F NMR yield aer 90 minutes for 12. 29 Additionally, iodoarene 5 could be recovered from the reaction mixture, with 70% recovery aer column chromatography in the case of entry 1 (Scheme 4), providing the opportunity to potentially re-use the material. Triuoromethylation of chlorothiophenol 13 gave comparable results, and 14 was obtained in 73% 19 F NMR yield (entry 2); typical yields for the triuoromethylation of aromatic thiols with reagent 2 have been reported in 72-91% yield. 3b Diphenylphosphine 15 (entry 3) also proved to be a viable substrate giving the triuoromethylated product 16 in 69% yield. 30 Oxytriuoromethylation of styrene 17 (entry 4) gave satisfactory yields of 66% respectively, compared to 93% for the same transformation using reagent 1. 31 Inspired by the work of Akita and co-workers, we investigated the visible light induced electrophilic triuoromethylation of triuoroborates, 19 and 20. 32 We obtained very favourable results using 1 mol% of [Ru(bpy) 3 ](PF 6 ) 2 photocatalyst giving the triuoromethylated alkene 21 in 86% yield when using 1.2 eq. of 4 for the potassium salt of styryltriuoroborate (entry 5). The equivalent reaction with 1 is reported in the literature to give a yield of 81% with 5 mol% of the same photocatalyst, however in our hands the 19 F NMR yield for this reaction was 35% aer 5 h, and 56% aer 15 h. We observed a similar trend a Data for reagent 1 and 2 taken from the literature. 3a,b X ¼ O1 or N1.</p><p>using para-methyl styryltriuoroborate which, under the literature reported conditions gave only 45% yield for 22 when reproduced in our lab vs. 81% reported in the literature with compound 1. Under the same conditions compound 4 gave 60% yield, which could be further improved to 99% when 1.9 eq. of 4 is used.</p><p>Considering reagent 4 is reminiscent of Shibata's uorinated Johnson reagent on the sulfoximine moiety, we were curious to explore whether this could be a second reactive site on the scaffold. 5 b-Keto ester 23 was chosen as a model substrate as this is known to react with Shibata's reagent to give the tri-uoromethylated product 24 in 74% yield. 5a Using the literature reported conditions, with 1.5 eq. of 4, DBU (1,8-diazabicyclo [5.4.0]undec-7) as base in CH 2 Cl 2 and stirring for 2 h, only 29% 19 F NMR yield of 24 was obtained. The 19 F NMR of the reaction mixture showed 73% of unreacted 4 as well as 30% iodoarene 5 and 42% sulfoximine 8. Thus, the CF 3 moiety at the iodine was transferred leaving the sulfoximine moiety intact. Stirring the reaction mixture longer did not lead to higher yields, however the yield could be improved by conducting the reaction under phase transfer conditions (entry 6), which gave moderate yields of 40%, whereas use of reagent 2 gives the desired product in 67% yield. 3b Finally, we were curious to explore the possibility of using the enantiopure sulfoximine reagent for asymmetric transformations. We rst turned our attention to tri-uoromethylation of chiral sulfonic acids, as the mechanism for this is well established to occur via protonation of the reagent by the substrate and coordination of the sulfonate to the iodine center, followed by reductive elimination to give the corresponding triuoromethylated sulfonic acid. 31 In order to enable kinetic resolution, we took 2 eq. of racemic 4 and reacted it under the standard conditions with 1 eq. of (1S)-(+)-10camphor sulfonic acid (entry 1, Scheme 4). Once the reaction was complete, the remaining reagent was recovered aer recrystallization of the reaction mixture, however no preferential reaction was observed, with 0% ee in recovered 4 observed by analytical chiral HPLC. Although this result was disappointing, we speculated that the stereogenic centre in camphorsulfonic acid was not close enough to the reactive centre to facilitate enantiodiscrimination. We next attempted the tri-uoromethylation of b-keto ester 23 under phase transfer conditions (entry 6). However, chiral analytical HPLC analysis of the puried reaction mixture showed only racemic 24. Although these results have so far proven unsuccessful, we aim to further investigate the possibility of asymmetric transformations by increasing the steric bulk on the sulfoximine group through</p><!><p>In conclusion we have described the facile synthesis of the new hypervalent iodine triuoromethylation reagent, 4, which to our delight shows stability and reactivity comparable to those of the parent reagents 1 and 2. Compound 4 could also be isolated in its enantiopure form and is, to the best of our knowledge, the rst described enantiopure hypervalent iodine compound bearing a transferable CF 3 moiety. This is a promising start to explore the possibility of enantioselective triuoromethylation of prochiral substrates, a longstanding challenge in electrophilic triuoromethylation chemistry. Investigations towards this objective are currently in our laboratories.</p><!><p>There are no conicts to declare.</p>