Dorian Dupommier

Michel Boisbrun

Gerald Monard

Corinne Comoy

Unexplored Vinylic Substituted 5-Benzylidenethiazolidine-2,4diones: Synthesis and DFT/NMR Stereochemical Assignment

Keywords: Benzylidenethiazolidine-2, 4-dione, Cross-coupling reaction, Combined DFT/NMR study, Stereochemistry, Wittig olefination, Energy calculations

HAL is

Introduction.

5-Benzylidenethiazolidine-2,4-dione (BTZD) 1 is a privileged scaffold 1 present in a wide range of bioactive molecules including antidiabetics, 2 antivirals, 3 anti-inflammatories 4 or antiproliferative compounds (Figure 1). [5][6][7][8][9]

Figure 1. Examples of bioactive compounds bearing a BTZD moiety

To access new bioactive molecules, several modifications to this structure could be envisaged.

N-alkylations of the TZD core and variation of the aryl moiety of BTZD represent the easiest and most explored methods. [START_REF] Chadha | Thiazolidine-2,4-Dione[END_REF][START_REF] Jain | Recent Developments and Biological Activities of Thiazolidinone Derivatives: A Review[END_REF][START_REF] Jain | Thiazolidine-2,4-Diones: Progress towards Multifarious Applications[END_REF] On the other hand, the vinylic functionalization has rarely been described which is surprising considering the density of the literature dealing with this structure. 1,[START_REF] Chadha | Thiazolidine-2,4-Dione[END_REF][START_REF] Jain | Recent Developments and Biological Activities of Thiazolidinone Derivatives: A Review[END_REF][START_REF] Jain | Thiazolidine-2,4-Diones: Progress towards Multifarious Applications[END_REF][13] Moreover, the very few reported vinylic modulations of the BTZD moiety resulted from Knoevenagel condensation involving aryl ketones (instead of aldehydes) and a thiazolidine-2,4-dione 2a (TZD, Scheme 1, path a). This methodology has two main drawbacks. Firstly, the observed yields starting from aryl ketones are much lower than those obtained when starting from aldehydes. [START_REF] Youssef | Reactions of 3-Substituted 5-Arylmethylene-1,3-Thiazolidin-2,4-Diones with Azide and Cyanide Ions[END_REF][START_REF] Kodimuthali | A New Synthesis of 2-(Hetero)Aryl-Substituted Pyrazines[END_REF] Secondly, the Knoevenagel condensation requires a large library of both substituted aryl ketones and TZD to access an important range of compounds. Our study aimed to overcome such difficulties and we report herein on our work concerning the development of the 6-functionalization of the BTZD scaffold (for numbering, see Scheme 1) which enables the introduction of a wide functional diversity starting from three easily accessible building blocks. We envisaged two main routes to prepare the expected substituted BTZD derivatives 1 (Scheme 1, paths b and c). The first sequence (path b) is based on the 6-unsubstituted BTZDs 3 (X = H) as key-intermediates obtained by the wellknown Knoevenagel condensation method using TZD 2a and various benzaldehydes. Pdcatalyzed cross-coupling reactions are powerful tools for C-C bond formation and so the resulting compounds 3 were then involved in a Heck coupling reaction to obtain the target 6substituted BTZDs 1. In addition, we aimed to synthesize 6-activated BTZDs 4 (e.g. X = OTf or Halogen) to involve them in Pd-catalyzed cross couplings such as the Stille or Suzuki reactions (path c). We aimed to achieve the synthesis of the desired derivatives 4 through a condensation of bis-anionic-TZD [2a-2Li] with benzoyl chlorides followed by an Oactivation.

Results and discussion

For this study, the 3-benzyl-5-(4-methoxybenzylidene)thiazolidine-2,4-dione 3b was selected as a model (Scheme 2). O-and N-protections were chosen to avoid side reactions and enable further functionalizations after selective deprotections. [START_REF] Mcomie | Demethylation of Aryl Methyl Ethers by Boron Tribromide[END_REF][START_REF] Jung | Quantitative Dealkylation of Alkyl Ethers via Treatment with Trimethylsilyl Iodide. A New Method for Ether Hydrolysis[END_REF][START_REF] Inaba | The First Total Synthesis of Deoxybouvardin and RA-VII, Novel Antitumor Cyclic Hexapeptides[END_REF] Thus, the Knoevenagel reaction of TZD 2a with 4-methoxybenzaldehyde (1.0 equiv.) in the presence of an excess of β-alanine (1.2 equiv.) and in acetic acid as solvent was found to result in the expected BTZD 3a with an excellent yield (83%). [START_REF] Bordessa | Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds[END_REF] The N-benzylation of 3a was then carried out by using benzyl bromide (1.1 equiv.) in the presence of cesium carbonate Cs 2 CO 3 (1.1 equiv.) to give 3b with an excellent yield (90%). Next, the 6-functionalization of 3b was investigated by means of the Heck cross-coupling reaction. Unfortunately, despite numerous attempts using a wide range of Heck cross-coupling conditions in the presence of PhX, including the Heck-Matsuda conditions using an aryldiazonium salt as an alternative to aryl iodide, [START_REF] Riemer | Iterative Arylation of Itaconimides with Diazonium Salts through Electrophilic Palladium Catalysis: Divergent β-H-Elimination Pathways in Repetitive Matsuda-Heck Reactions[END_REF] no trace of the desired 6-phenyl-BTZD 1a could be detected (Scheme 2).

Scheme 2. 6-Functionalization of 3b involving a Heck coupling reaction.

In the light of these results, we envisaged an alternative 6-functionalization sequence starting from the activated BTZD 4. The latter could be involved in Stille and Suzuki cross-coupling reactions (Scheme 1, path c). To access 4, the first step was a lithiation of N-benzyl TZD 2b 21 using a slight excess of n-butyllithium (n-BuLi, 1.1 equiv.) in tetrahydrofuran (THF). [START_REF] Fujishita | Compounds Having Anti-Hepatitis C Virus Effect[END_REF] The lithium salt [2b-Li] was then quenched by adding 4-methoxybenzoyl chloride as an electrophile. A meticulous optimization of the condensation temperature was achieved to lead to the expected enol 5 with a fair yield (55%, Scheme 3).

Scheme 3. Preparation of the enol 5.

No information has been reported in the literature concerning the stereochemistry of the double bond of the reported structure [START_REF] Fujishita | Compounds Having Anti-Hepatitis C Virus Effect[END_REF] and because the intramolecular hydrogen bond may occur in enol 5, we assumed that it should be an (E)-configuration. Our hypothesis was confirmed by X-ray crystallography analysis which indeed showed the presence of an exocyclic C-C double-bond (d C-C = 1.377 Å) with the expected stereochemistry and a planar conjugated system (Scheme 3 and see Supplementary Information Section 1). The tautomeric equilibrium between the enol 5 and the ketone 5' (Figure 2) was also observed by 1 H-NMR spectroscopy. In CDCl 3 as solvent, the equilibrium was fully displaced in favor of the enol form 5 similarly to the solid-state, while both 5 and 5' tautomers were identified in more polar solvents. In particular, the α-dicarbonyl hydrogen atom H-5 was clearly observed as a strongly deshielded signal in DMSO-d 6 , CD 3 CN or acetone-d 6 (for 1 H-NMR spectra and details see Supplementary Information Section 2). To begin the exploration of the synthetic path c, the synthesis of vinylic (pseudo)halide precursors 4a-c was investigated (Table 1). Firstly, the reaction carried out with trifluoromethanesulfonic anhydride (Tf 2 O) in the presence of pyridine as base at 0 °C was unsuccessful since no conversion of 5 was observed (entry 1). A stronger base, n-BuLi, at -80 °C was used (entry 2) because the complete deprotonation of the enol 5 could improve the triflate formation. The modification was however disappointing and did not alter the result.

Finally, the use of PhNTf 2 was envisaged (entry 3) because it is known to be a more selective O-triflation agent than its related anhydride. To enhance the reaction conditions, triethylamine (Et 3 N) was used at 0 °C in the presence of a catalytic amount of dimethylaminopyridine (DMAP, 5 mol%). The result was once more disappointing, as no conversion was observed. Therefore, we modified our strategy and focused on the replacement of the hydroxyl group by a halide. Unfortunately, the halogenation reactions using phosphorus trihalide PX 3 (X = Cl, Br) and the Appel conditions (PPh 3 and CBr 4 ) were unsuccessful since 5 was recovered unchanged (entries 4-6). It thus appeared that the use of phosphorus oxyhalide POX 3 (X = Cl, Br) was a far more interesting idea. Indeed, when POCl 3 or POBr 3 were used in excess (10.0 equiv., entries 7-8) in the presence of DIPEA, partial conversion of 5 was observed (TLC monitoring). The 6-chloro-BTZD 4c was isolated after column chromatography in moderate yield (42%) while the purification of its brominated analog led to a complete degradation of 4b. The use of POCl 3 as both reagent and solvent [START_REF] Woll | Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy[END_REF] at 110 °C for 6 to 18 hours allowed for a significant increase of the yield (entries 9-12). When a large excess of POCl 3 (24.0 equiv.) was used, 4c was isolated with a good yield (71%, entry 9). However, higher excesses of POCl 3 did not lead to any improvements (60 and 63% yield respectively for 38.0 and 183.0 equiv., entries 10 and 11). Finally, to avoid the partial degradation of the 6-chloro BTZD 4c during the column chromatography, an in-situ distillation of the excess of POCl 3 followed by a classical aqueous work up provided the clean 4c, according to 1 H NMR, in an almost quantitative yield. It is noteworthy that 4c was obtained as a mixture of inseparable isomers (ratio: 69/31 estimated by 1 H NMR based on the crude mixture, see NMR spectra in Supporting Information) while the (E)-and (Z)-isomer attribution according to NMR spectrum was deemed impossible. To overcome this problem, we computed the theoretical 13 C NMR spectra for both (E)-and (Z)-4c, using the formalism described by Lodewyk, Jain, Rablen et al. [START_REF] Rablen | A Comparison of Density Functional Methods for the Estimation of Proton Chemical Shifts with Chemical Accuracy[END_REF][START_REF] Jain | Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets[END_REF][START_REF] Bally | Quantum-Chemical Simulation of 1 H NMR Spectra. 2. † Comparison of DFT-Based Procedures for Computing Proton-Proton Coupling Constants in Organic Molecules[END_REF][START_REF] Lodewyk | Computational Prediction of 1 H and 13 C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry[END_REF] and the Gaussian09 software. 28 For this purpose, we focused our study on the 1 H-decoupled 13 C NMR spectra because of the higher resolution for all the signals, the absence of overlaps and the simple singlet signals when compared to the 1 H NMR spectra. The theoretical spectra were obtained in two steps for all compounds. Firstly a full geometrical optimization at the B3LYP/6-311+G(2d,p) level was performed in a vacuum, ensuring that no imaginary frequency remained. Secondly, a single point energy calculation was performed at the mPW1PW91/6-311+G(2d,p) level using the Gauge-Independent Atomic Orbital (GIAO) 29,[START_REF] Cheeseman | A Comparison of Models for Calculating Nuclear Magnetic Resonance Shielding Tensors[END_REF] method and the universal solvent model (SMD) [START_REF] Marenich | Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions[END_REF] with a dielectric constant corresponding to chloroform (ε = 4.7113). The raw isotropic nuclear constants obtained in this way were converted into chemical shifts using the adequate approximate linear relationships. [START_REF] Lodewyk | Computational Prediction of 1 H and 13 C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry[END_REF] These data were useless because the simple linear regression following the equation δ exp = f(δ th ) did not enable us to satisfactorily discriminate between both stereoisomers (see Supplementary Information Section 3). Therefore, the data had to be interpreted further to enable an isomer attribution. This was done simply by calculating for each carbon of 4c (i) the difference between the experimental chemical shifts of the major and the minor isomers, (ii) the difference between the theoretical chemical shifts of the (Z)-and (E)-isomers. The sign of the product (i)×(ii) is relevant and its absolute value was particularly high when dealing with the carbon atoms around the double bond, such as the carbon atoms numbered C-3, C-11 and C-12 (Table 2). Indeed, the chemical shifts of these carbon atoms are directly influenced by the stereochemistry of 4c. As a result, for these three carbons, values of (i) × (ii) were found to be high and positive which is evidence that the theoretical (Z)-isomer and the experimental major isomer are in fact the same compound (for full data see Supplementary Information Section 3). a 4c was used as a pure mixture of (Z/E)-isomers with the ratio 69/31 and was drawn as an isomer mixture (wavy bond). For the purpose of clarity, the representation of the relative positions of Cl and S held by the double-bond of 4c as in its major form was chosen. By default, the same representation for 1b was chosen. b Isolated yields after silica gel chromatography purification.

Surprisingly, starting from (Z/E)-4c, 1b was isolated as a single isomer (for the crude 1 H NMR spectrum see Supplementary Information Section 4) showing a highly deshielded signal at 8.24 ppm in 1 H NMR (CDCl 3 , 400 MHz) which was assigned to the H16 hydrogen atom (Figure 3). To explain this level of deshielding, the theoretical chemical shifts for H16 atom in both (Z)-1b and (E)-1b were computed by using the above-described calculation method. A significant difference in the theoretical chemical shifts of both isomers was highlighted ( th = 6.52 ppm versus  th = 8.40 ppm, Figure 2). This level of difference could be attributed to two phenomena -the positioning of H16 inside the anisotropy cone of the TZD carbonyl in (Z)-1b compared to (E)-1b and the establishment of a hydrogen bond between this hydrogen atom and the adjacent carbonyl. This kind of unconventional H-bonding between an unactivated C-H moiety and the lone pair of an adjacent double-bonded oxygen was studied by Sureshan et al. [START_REF] Vibhute | Model Molecules to Classify CH⋯O Hydrogen-Bonds[END_REF] It should be noted that  th,H16 of 1b was very close to the experimental value ( exp = 8.24 ppm,  th = 8.40 ppm), while  th,H16 was far more shielded (6.52 ppm)

which is in accordance with Sureshan's work. Additional evidence for this (Z) stereochemistry of 1b was that the linear regression, following the equation δ H,exp = f(δ H,th )

showed a very good correlation coefficient for the (Z)-isomer, while the values were quite lower for the (E)-isomer, indicating a lower correlation trend (for details see Supplementary Information Section 3.2). After study of these computed results, the Stille-resulting derivative 1b was unambiguously assigned to be the (Z)-isomer. It should be emphasized that, according to the CIP rules, the priority of the substituents between (Z)-4c and (Z)-1b changed, suggesting an isomerization of the (Z)-isomer of 4c during the Stille reaction. This means that the relative position of substituents on the BTZD double bond in (Z)-4c and (Z)-1b was inverted, although the (Z)-designation was maintained in both compounds. Information Section 5). [START_REF] Canovese | Palladium(0)-Catalyzed Cis-Trans Alkene Isomerizations[END_REF][START_REF] Canovese | Synthesis, stability and reactivity of palladium(0) olefin complexes bearing labile or hemi-labile ancillary ligands and electron-poor olefins[END_REF] Based on the latter results, we extended the scope of the 6-functionalization using various trin-butylstannane derivatives 6 as Stille coupling partners (see Experimental Section for the preparation of commercially unavailable stannanes 6). The optimized procedure gave good isolated yields of alkenyl-or (het)aryl derivatives 1b-g (50-67%, Table 4) except for 1c (21%, entry 2). As mentioned above, a partial degradation of 1b was observed during the purification step, even when a reverse phase column was used. In addition to the isolated yield of 1, we also evaluated the efficiency of the coupling sequence, prior to column chromatography, by directly measuring the yield on the crude mixture using duroquinone as internal reference. [START_REF] Pauli | Importance of Purity Evaluation and the Potential of Quantitative 1 H NMR as a Purity Assay: Miniperspective[END_REF] As a result, such 1 H NMR analyses displayed much better yields for derivatives 1b,d-e compared to isolated yields, showing that some degradation occurred on the silica gel (entries 1, 3-4). By contrast, no trace of degradation was observed for 1f-g (entries 5-6). The (Z/E) ratio of 1b-g was next investigated by using quantum chemical calculations previously described for 4c or 1b (for details see Supplementary Information Section 3). As for vinyl-BTZD 1b, allyl analogue 1c was found as a single (Z)-isomer concerning the BTZD moiety, while the stereochemistry of the introduced protected allylamine was found to be unchanged, as evidenced by the coupling constant (J = 15.6 Hz, see Experimental Section). Regarding the (Z/E) ratio of the (hetero)aromatic compounds 1d-g, partial changes were observed compared to ratio of 4c. a 4c was used as a pure mixture of (Z/E)-isomers with the ratio 69/31. For the purpose of clarity, the representation of the relative positions of the double-bond substituents was depicted as in its major form except for 1e and 1g. b Yields were determined by 1 H NMR using duroquinone as an internal standard. c (Z/E) ratio was determined by 1 H NMR based on the crude mixture.

A main drawback of the Stille reaction conditions is the use of toxic tin reagents, [START_REF] Egorova | Toxicity of Metal Compounds: Knowledge and Myths[END_REF] which are difficult to get rid of and need fastidious purifications. On the opposite, Suzuki crosscoupling, [START_REF] Miyaura | Stereoselective Synthesis of Arylated (E)-Alkenes by the Reaction of Alk-1-Enylboranes with Aryl Halides in the Presence of Palladium Catalyst[END_REF][START_REF] Lennox | Selection of Boron Reagents for Suzuki-Miyaura Coupling[END_REF] frequently used in pharmaceutical industry, [START_REF] Brown | Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?[END_REF] is a related reaction that involves organoboron compounds which are often easier to remove and show low toxicities. To assess the efficiency of this reaction, 4c was involved in a Suzuki cross-coupling (Table 5). Firstly, common conditions were explored using the (4-formylbenzene)boronic acid as coupling partner and Pd(PPh 3 ) 4 (5 mol%) as a catalyst in toluene/EtOH/water (6:3:2 v/v) which allowed the complete dissolution of 4c, at 50 °C, in the presence of sodium carbonate (Na 2 CO 3 , entry 1). The observed result was quite disappointing with only 33% of 6-formylphenyl-BTZD 1h

(measured yield by 1 H NMR) in the presence of unchanged 4c. Using twice the initial amount of Na 2 CO 3 led to a slight yield improvement of 1h (39%, entry 2), while the replacement of Na 2 CO 3 by K 2 CO 3 or KF showed no significant effect on the result (31 and 30% respectively, entries 3 and 4). When the solvent mixture (toluene/EtOH/water) was replaced by DMF/H 2 O

(1:1 v/v), no trace of 1h was detected and the substrate 4c was recovered unchanged (entry 5).

The use of an additional ligand (PPh 3 or XPhos, 10 mol%) only resulted in poor results (9 and 10% 1 H NMR yield respectively, entries 6, 7). Next, a few catalysts were assessed as a replacement of Pd(PPh 3 ) 4 (entries 8-11). The use of the 2 nd generation Buchwald catalyst PdXPhos G2 gave rise to a by-product 7a (17% 1 H NMR yield, entry 8), while no increase in yield of 1h was observed. According to MS and NMR spectra, 7a was suggested to result from the addition of the co-solvent EtOH on the chlorinated position in 4c. In contrast, very good results were observed by using Pd(dppf)Cl 2 as catalyst. In this case, the conversion of 4c was almost complete and 1h was obtained in 92% 1 H NMR yield in the presence of traces of 7a (5% 1 H NMR yield, entry 9). We next studied the influence of the reactional temperature.

Firstly, when the temperature of initial conditions was increased to 110 °C, the yield of 1h was significantly improved (33 vs 67% 1 H NMR yield, entries 1 and 10 respectively).

Nevertheless, the byproduct 7a was also obtained with an increased yield (33% 1 H NMR yield). Finally, the best conditions were based on the conditions stated in entry 9, by using Pd(dppf)Cl 2 as a catalyst to reduce the formation of 7a, and at 110 °C to enhance the yield of 1h (entry 11). As a result, and according to TLC monitoring, the expected 6-formylphenyl-BTZD 1h was obtained after only 3 hours in quantitative 1 H NMR yield without any trace of 7a. a 4c was used as a pure mixture of (Z/E)-isomers with the ratio 69/31. For the purpose of clarity, the representation of the relative positions of the double-bond substituents was depicted as in its major form. b Yields were determined by 1 H NMR using duroquinone as internal standard. We next extended the scope of the Suzuki coupling to various boronic acid and esters (Table 6). Derivative 1h was thus prepared as previously stated (Table 5, entry 11) and isolated in an excellent 96% yield as a pure compound after classical washing work up without further purification. The (Z/E) ratio of 1h was assigned as a 63/37 mixture by using quantum chemical calculations as previously described for 4c (for details see Supplementary Information Section 3.8). It should be noted that, considering the CIP rules, the major stereoisomer of 1h identified as (Z)-1h holds the same double bond geometry as (E)-4c, the minor stereoisomer of the substrate 4c. Functionalization of BTZD moiety using phenyl-or pmethoxyphenylboronic acids as coupling partners also gave good results. 1a,i were prepared with a very good 1 H-NMR yield (90 and 76% respectively, entries 2 and 3) but showed a lower isolated yield (76 and 49% isolated yields respectively) because of partial degradation upon silica gel purification and the formation of the by-product 7a. The introduction of heteroaryl units was explored using thienyl-, indolyl-or pyridinylboronic acids (entries 4-6, and 9). With EtOH as the co-solvent, the expected thienyl derivatives 1j-k were obtained in quite modest isolated yields (26 and 29% respectively) while 7a was found to be the main product (62 and 58% isolated yields respectively) which highlights the low reactivity of these two thienylboronic acids in these cross-coupling conditions. The case of the reaction leading to 1l when using N-Boc-indolylboronic acid as the coupling partner was far more critical in that no trace of this product was detected (entry 6, quantitative yield for 7a). In contrast, the preparation of (2-fluoropyrinin-3-yl) compound 1m occurred efficiently with a good 61% isolated yield (entry 9) but still with a significant amount of 7a (35% isolated yield). To reduce the formation of 7a and increase the yield of expected compounds 1, the replacement of EtOH by a more hindered alcohol was investigated. The use of isopropanol (i-PrOH) as the co-solvent was found to have a very low effect on the preparation of the indolyl derivative 1l, since 7b remained the main product (90% isolated yield) with only 10% of 1l ( 1 H NMR yield, entry 7). In more efficient conditions, the use of t-butanol (t-BuOH) enables 1l to be obtained with an impressive increased 1 H NMR yield (61%) which was successfully isolated as a pure mixture of (Z)-and (E)-isomers (54% isolated yield, Z/E: 30/70, entry 8). Moreover, as expected, no trace of 7c resulting from the addition of t-BuOH to 4c was detected. In pyridine series, the replacement of EtOH by i-PrOH afforded 1m in a drastically increased yield (91 and 85% 1 H NMR and isolated yields respectively, entry 10) without any trace of 7b. Finally, in order to compare the efficiency of the Stille and the Suzuki cross-couplings, a preparation of aminoallylic derivative 1c was examined by involving the pinacolboronic ester 42 (E)-8.

According to the optimized conditions, 1c was prepared with very good yields depending on the nature of the alcohol co-solvent (66 and 71% isolated yields, entries 11 and 12) while only 21% of 1c were obtained by using the Stille coupling (entry 2, table 4). It should be noted that no trace of adduct 7a or 7c was detected whether with EtOH or t-BuOH. As well as with the Stille reaction, 1c was isolated as a single (Z)-isomer on the exocyclic TZD unsaturation (for the crude NMR spectrum see Supporting Information Section 4) while the stereochemistry of the introduced protected allylamine was also unchanged. Overall, Suzuki cross-coupling allowed the preparation of various 6-aryl or heteroaryl BTZD 1a,c,h-m in modest to excellent isolated yields (up to 96%) and the use of a more hindered alcohol as co-solvent seems to allow an easier formation of 1. a 4c was used as a pure mixture of (Z/E)-isomers with the ratio 69/31. For the purpose of clarity, the representation of the relative positions of the double-bond substituents was depicted as in its major form. b Yields were determined by 1 H NMR using duroquinone as internal standard.

c (Z/E) ratio was determined by 1 H NMR based on the crude mixture. Having obtained these results, our next step was to rationalize the selectivity of the reaction for each of these products. To this end, we computed the Δ r H 0 of the isomerization of 1a-m from the (E)-to the (Z)-isomer. This was carried out on Gaussian09 28 by the means of a full geometrical optimization followed by a frequency calculation (T = 373.15K, P=1atm) with the DFT functionals B3LYP, M06-2X [START_REF] Zhao | The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals[END_REF] or wB97X-D [START_REF] Chai | Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections[END_REF] and the universal solvent model (SMD) [START_REF] Marenich | Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions[END_REF] with a dielectric constant corresponding to toluene (ε = 2.3741) or DMF (ε = 37.219). The obtained enthalpies were then transformed into (Z/E) ratio using the Boltzmann equation (see Supplementary Information Section 7). The results of these calculations were in good agreement with the stereoselectivity obtained for the products, especially with the recommended level ωB97X-D/Def2TZVP, [START_REF] Bursch | Best-Practice DFT Protocols for Basic Molecular Computational Chemistry[END_REF] even if the ratios of 1d, 1f and 1g were less accurate than the others (Figure 4). with 2-bromo-para-methoxyacetophenone (1.0 equiv.) in THF (Scheme 4). [START_REF] Zask | Synthesis of 3-Mercapto-2(5H)-Furanones via Reaction of Dilithio-2,4-Thiazolidinedione with α-Halo Ketones[END_REF] The (E)stereochemistry was attributed to compound 9 through X-ray diffraction analysis (see Supplementary Information Section 1). The chemo-controlled oxidation by sodium dichromate of 9 [START_REF] Harding | Selective Oxidation of Allylic Alcohols with Chromic Acid[END_REF] afforded the expected aldehyde 10 in 87% yield. (see Experimental Section for the preparation of phosphonium ylides) successfully led to the desired 6-alkenyl BTZD 1n-q with good to excellent isolated yields (56 to 99% isolated yield, Table 7). The stereochemistry of 1n-q was assigned as a single (E)-stereoisomerism for the formed alkenyl double bond according to the 1 H NMR coupling constants (J~16 Hz) and as a single (Z)-stereoisomerism for the benzylidene double bond by using the previously described method for 1b and comparing quantum chemical calculations to experiment NMR values (for details see Supplementary Information Section 3).

Conclusion.

In this paper, we have proposed two strategies including a Pd-catalyzed coupling reaction or a Wittig olefination as key-steps to prepare a library of 6-aryl-, heteroaryl-or alkenyl BTZD scaffolds 1a-m and 1n-q. After the development of the synthesis of the chlorinated precursor 4c, the 6-functionnalization of BTZD was proved more efficient using the Suzuki crosscoupling than the Stille reaction. Particular care was taken to assign the stereochemistry of those derivatives 1a-m through a combined experimental/DFT-simulated NMR spectra methodology. On the other hand, the Wittig reaction led to the targeted 6-alkenyl BTZD 1n-q with excellent yields and with a high stereoselectivity since only the (2E,4Z)-diastereoisomers were detected. With this work, we have opened up a new unexplored chemical direction and hope that this will pave the way for the discovery of new bioactive BTZD compounds.

Experimental Section.

All reactions were performed under argon atmosphere. Melting points (M.p.) were measured on a Kofler bench and were uncorrected. [START_REF] Gottlieb | NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities[END_REF] or the signal for CFCl 3 for 19 F. [START_REF]The Single Fluorine Substituent[END_REF] The NMR quantification were carried out in the presence of an internal standard (duroquinone TraceCERT ® for spectra recorded in CDCl 3 ). (Z/E) ratios of compounds were estimated by

3-Benzylthiazolidine-2,4-dione (2b):

To a solution of thiazolidine-2,4-dione 2a (TZD, 5.00 g, 42.69 mmol) in DMF (150 mL) were added K 2 CO 3 (11.80 g, 85. 38 mmol) and BnBr (5.60 mL, 46.96 mmol). The reaction mixture was stirred 3 hours at room temperature. After filtration of the suspended solid, the filtrate was diluted with EtOAc (360 mL), washed with water (3 × 300 mL) then with an aqueous saturated solution of NaCl (300 mL). The aqueous layer was saturated using NaCl and extracted with EtOAc (3 x 20 mL). The organic layers were combined and were dried (MgSO 4 ), the solvents were removed under reduced pressure.

After purification by flash column chromatography (eluent: cyclohexane/EtOAc 100/0 to 20/80 in 20 minutes, then isocratic mode for 20 minutes) the expected benzylated TZD 2b was obtained as a white powder (6.64 g, 32.0 mmol, 75%). 1

(Z)-3-Benzyl-5-(1-(4-methoxyphenyl)allylidene)thiazolidine-2,4-dione (1b):

This compound was prepared according to the general procedure for the Stille reaction starting from the commercial tri-n-butyl(vinyl)stannane. After CH 3 CN evaporation, the residue was purified by flash chromatography on neutral alumina (eluent: cyclohexane/EtOAc 100/0 to 95/5 in 20 minutes then isocratic mode for 10 minutes) yielding (Z)-1b (pure (Z)-isomer) as a yellow oil (0.115 g, 0.327 mmol, 59%). IR (ATR): ν (cm

(Z/E)-3-Benzyl-5-((4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methylene)thiazolidine-

2,4-dione (1d):

Preparation of the tri-n-butyl (3,4,5-trimethoxyphenyl)stannane (6b): To a solution of 1bromo-3,4,5-trimethoxybenzene (2.00 g, 8.09 mmol) in THF (20 mL) at ˗80 °C was added n-BuLi solution (1.6 M in hexanes, 5.6 mL, 8.90 mmol). After 30 minutes, the temperature was allowed to warm up to room temperature and n-Bu 3 SnCl (2.4 mL, 8.90 mL) was added. After refluxing for 30 minutes, the reaction mixture was hydrolyzed. EtOAc (30 mL) was added and the organic layer was washed with an aqueous HCl 1 M solution and water (pH=4). The organic layer was dried (MgSO 4 ) and solvents were removed under reduced pressure. After purification by flash column chromatography (eluent: cyclohexane/EtOAc 100/0 to 90/10 in 20 minutes, then isocratic mode for 20 minutes) 6b was obtained as a colourless oil (1.40 g,

mmol, 38%

).

(CH 3 ), 44.9 (2 peaks, CH 2 ).

(Z/E)-5-(Benzo[b]furan-2-yl(4-methoxyphenyl)methylene)-3-benzylthiazolidine-2,4-

dione (1e):

Preparation of the 2-tri-n-butylstannylbenzo[b]furane (6c): To a solution of benzo[b]furane

(1.00 g, 8.46 mmol) in THF (25 mL) at 0 °C was added n-BuLi solution (1.6 M in hexanes, 5.8 mL, 9.31 mmol). After stirring for 1 hour, the temperature was cooled down to -80 °C and n-Bu 3 SnCl (2.5 mL, 9.2 mmol) was added. After stirring for additional 30 minutes, the reaction mixture was hydrolyzed, diluted with EtOAc (50 mL) and washed with water (3 × 30 mL). The organic layer was dried (MgSO 4 ) and the solvents were removed under reduced pressure. After purification by flash column chromatography (eluent: cyclohexane/EtOAc 100/0), 6c was given as a colourless oil (3.11 g, 7.64 mmol, 90%). ). Other analyses were in accordance with the literature. [START_REF] Akram | Gold(I)-Catalyzed Cross-Coupling Reactions of Aryldiazonium Salts with Organostannanes[END_REF] The compound 1e was prepared according to the general procedure for the Stille reaction with the tri-n-butylstannane 6c. After the purification of the crude compound ((Z/E) ratio =

(Z/E)-3-Benzyl-5-((4-methoxyphenyl)(thiophen-2-yl)methylene)thiazolidine-2,4-dione (1f):

This compound was prepared according to the general procedure for the Stille reaction with the commercially available tri-n-butyl(thiophen-2-yl)stannane. The crude compound 1f dissolved in CH 2 Cl 2 (30 mL). This organic layer was washed with an aqueous 1 M NaOH solution (2 × 30 mL), dried (MgSO 4 ), filtered and the solvents were removed under reduced pressure. The expected 11b was obtained as a white powder (1.47 g, 4.66 mmol, 82%).

((Z/E) ratio =

Associated Content

email: dorian.dupommier@vscht.cz Gérald Monard -Université de Lorraine, CNRS, CRM2, F-54000, Nancy, France orcid.org/0000-0002-3378-3481 email: gerald.monard@univ-lorraine.fr

Scheme 1 .

 1 Scheme 1. Synthetic pathways to 6-functionalization of BTZDs 1.

Figure 2 .

 2 Figure 2. Tautomeric equilibrium 5/5'.

Figure 3 .

 3 Figure 3. Comparison between the computed chemical shifts for H16 in (E/Z)-1b and the experimental one.

c 1 M

 1 aqueous solution. d 3.0 equiv. of base. e Reaction solvent: DMF/H2O. f Time of completion.

Figure 4 .

 4 Figure 4. Comparison between the computed and experimental (Z) fraction of the BTZD products.

Scheme 4 .

 4 Scheme 4. Synthesis of the target aldehyde 10.

(

  30 mL). The organic layer was washed with water (3 × 20 mL) and with an aqueous saturated solution of NaCl (20 mL), dried (MgSO 4 ) and the solvents were removed under reduced pressure.(Z/E)-4-((3-Benzyl-2,4-dioxothiazolidin-5-ylidene)(4-methoxyphenyl)methyl)benzaldehyde (1h): This compound was prepared according to the general procedure for the Suzuki reaction with the commercially available (4-formylbenzene)boronic acid and EtOH as a co-solvent. After the purification of the crude compound ((Z/E) ratio = 63/37) by flash chromatography (eluent: cyclohexane/EtOAc 100/0 for 20 minutes then to 85/15 in 20 minutes) 1h was isolated as a pure mixture of the two stereoisomers as a yellow oil (0.228 g, 0.533 mmol, (Z/E) ratio = 74/26, 96%

The derivative 1c was(E)- 5 -( 2 -

 52 prepared according to the general procedure of the Suzuki crosscoupling starting from the pinacolborane (E)-8 in t-BuOH as co-solvent. The expected derivative (Z)-1c (pure (Z)-isomer) was isolated by flash chromatography in reverse phase (eluent: H 2 O/MeOH 50/50 to 10/90 in 20 minutes, then isocratic mode for 10 minutes) as a yellow solid (0.189 g, 0.394 mmol, 71%). Hydroxy-1-(4-methoxyphenyl)ethylidene)thiazolidine-2,4-dione (9): To a solution of TZD 2a (10.00 g, 85.4 mmol) in THF (450 mL) at -80 °C was added dropwise the solution of n-BuLi (1.6 M in hexanes, 121 mL, 187.9 mmol). The temperature was allowed to warm up to 0 °C (ice bath) and maintained for 1 hour. After cooling to -80 °C, a solution of 2bromo-1-(4-methoxyphenyl)ethan-1-one (19.6 g, 85.4 mmol) in THF (25 mL) was added to the reaction mixture. The temperature media was allowed to rise to room temperature in 2 hours, then the reaction was quenched by adding an aqueous HCl 1 M solution (pH=2).

Table 1 . Synthesis of 4a-c precursors starting from the enol 5.

 1

	entry	Activation reagent (n equiv.)	Base (m equiv.)	T (°C)	t (h)	Isolated Yield
						(%) (4a-c)
	1	Tf 2 O (1.4)	Pyridine (6.0)	0	1	0 (4a) a
	2	Tf 2 O (1.4)	n-BuLi (1.1)	-80	2	0 (4a) a,b
	3	PhNTf 2 (1.4), DMAP (0.05)	Et 3 N (1.4)	0	1	0 (4a) a
	4	PBr 3 (1.4)	-	rt c	16	0 (4b) a
	5	PCl 3 (1.4)	-	rt	16	0 (4c) a
	6	PPh 3 , CBr 4 (1.2)	-	rt	16	0 (4b) a
	7	POBr 3 (10.0)	DIPEA (1.7)	rt	3	0 (4b) d
	8	POCl 3 (10.0)	DIPEA (1.7)	rt	3	42 (4c)
	9	POCl 3 (24.0)	DIPEA (1.7)	110	6	71 (4c) e
	10	POCl 3 (38.0)	DIPEA (1.7)	110	6	60 (4c) e
	11	POCl 3 (183.0)	DIPEA (1.7)	110	18	63 (4c) e

a No conversion. b THF was used as solvent. c rt: room temperature. d Partial degradation and incomplete conversion of 5. e POCl3 was used as reagent and solvent.

21

f Isolated pure without column purification.

Table 2 . Experimental and theoretical 13 C NMR data for both isomers of 4c. Major isomer (Z)-4c. Carbon a δ th b (ppm) Δ th δ exp c,d (ppm) Δ exp Δ th ×Δ exp (Z)-4c (E)-4c δ(Z) th -δ(E) th b Major isomer Minor isomer δ(major) exp -δ(minor) exp c

 2 As numbered in the Gaussian09 input file. b th = theoretical. c13 C NMR spectra realized at 100.6 MHz in CDCl3. d exp = experimental.

	1,5	111.47 112.76	-1.29	113.48	114.36	-0.88	1.14
	2,4	131.93 129.76	2.175	131.35	130.17	1.18	2.57
	3	125.58 129.60	-4.02	127.16	129.9	-2.74	11.02
	6	161.69 161.11	0.58	161.84	162.81	-0.97	-0.56
	11	152.59 144.46	8.13	143.55	136.95	6.60	53.66
	12	124.67 123.45	1.22	122.38	119.68	2.70	3.29
	13	159.86 160.79	-0.93	161.76	161.63	0.13	-0.12
	14	166.51 166.31	0.20	166.49	166.42	0.07	0.01

a

Table 3 . Stille cross-coupling optimization on 4c.

 3

	Entry a	Ligand	T (°C)	Isolated yield (%) b
	1	Pcy 3	rt	19
	2	Pcy 3	80	25

Table 4 . Extended Stille cross-coupling conditions.

 4

			Yield (%)
	Entry a	Product	R	(Z/E) ratio c
			isolated (NMR) b
	1	1b	59 (90)	100/0
	2	1c	21 (30)	100/0
	3	1d	60 (95)	45/55
	4	1e	50 (76)	86/14
	5	1f	67 (69)	48/52
	6	1g	59 (60)	58/42

Table 5 . Optimization of the Suzuki cross-coupling on 4c.

 5

							1 H-NMR Yield, % b
	Entry a	Pd-catalyst	Base	Ligand	T (°C) t (h)
							1h	7a
	1	Pd(PPh 3 ) 4	Na 2 CO 3 c	-	50	18	33	0
	2	Pd(PPh 3 ) 4	Na 2 CO 3 c,d	-	50	18	39	0
	3	Pd(PPh 3 ) 4	Cs 2 CO 3 c	-	50	18	31	0
	4	Pd(PPh 3 ) 4	KF c	-	50	18	30	0
	5 e	Pd(PPh 3 ) 4	Na 2 CO 3 c	-	50	18	0	0
	6	Pd(PPh 3 ) 4	Na 2 CO 3 c	PPh 3	50	18	9	0
	7	Pd(PPh 3 ) 4	Na 2 CO 3 c	XPhos	50	18	10	0
	8	PdXPhos G2	Na 2 CO 3 c	-	50	18	27	17
	9	Pd(dppf)Cl 2	Na 2 CO 3 c	-	50	18	92	5
	10	Pd(PPh 3 ) 4	Na 2 CO 3 c	-	110	18	67	33
	11	Pd(dppf)Cl 2	Na 2 CO 3 c	-	110	3 f	100	0

Table 6 . Extended Suzuki cross-coupling conditions to various boronic derivatives.

 6

					Isolated (NMR) Yield, % b
	Entry a	R 1	R 2	R 3
					Product	(Z/E) ratio c by-product 7
	1		H	Et	1h, 96 (100)	63/37	7a, 0

Table 7 . Synthesis of 6-alkenyl BTZD 1n-q.

 7

	Entry	Product	Isolated Yield, %
	1	1n, R 1 = H, R 2 = CO 2 Me	99
	2	1o, R 1 = H, R 2 = COMe	56
	3	1p, R 1 = Me, R 2 = CO 2 Me	76

  1 H,13 C and[START_REF] Bordessa | Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds[END_REF] F NMR spectroscopic data were recorded on a Bruker Advance III 200 (200, 50.3 and 188.2 MHz respectively), a Bruker Advance III 400 (400, 100.6 and 376.4 MHz respectively) or a Bruker Advance III HD 300 (300.1 and 75.5 MHz respectively). Chemical shifts were reported in ppm (δ) and were measured related to the signals for the residual solvents

  High resolution mass spectra (HRMS) were recorded on a Bruker MicrOTOFq ESI/QqTOF apparatus and low-resolution spectra in electronic impact (GC-EI)

	were recorded on a Shimadzu QP2010 coupled with a gas chromatography apparatus
	equipped with a DB5-MS UI column (length: 30 m, width: 0.25 mm, thickness of the film:
	0.25 µm). Infrared spectra (IR) were recorded on a Shimadzu IRAffinity-1 equipped with an
	ATR PIKE Technologies model gladiAT. Heat-On™ block systems were used for reaction
	that required heating. Reaction completion was checked by TLC using 60 F 254 or 60-RP-18
	F 254 S (Merck) plates and were revealed with UV light (254 nm). Flash column
	chromatography were achieved on a Grace Reveleris® equipped with 40 µm silica or C 18 -

1

H NMR based on the crude mixture. Note that variation of this (Z/E) ratio could be observed after purification step, consequently, NMR spectra given in Supplementary Information could display a modified ratio. grafted silica cartridges. Anhydrous THF and MeOH were freshly collected on a MBRAUN MB-SPS-800 solvent purification system. Dichloromethane was distilled over CaH 2 and stocked on 4 Å molecular sieve. DMF was also stocked on 4 Å molecular sieve. n-BuLi was used as a commercial 1.6 M solution in hexanes (always titrated prior to use). Other commercial reagents were used without further purification.

  It was allowed to warm up to room temperature over 30 minutes and the temperature was hold for 1 additional hour. The reaction was then quenched with AcOH (3 mL) and the solvents were removed under reduced pressure. The obtained yellow gum was To Pd(PPh 3 ) 4 (0.032 g, 0.028 mmol) and CuI (0.010 g, 0.056 mmol) were added a solution of 4c (0.200 g, 0.555 mmol) in DMF (2 mL), JohnPhos ligand (0.016 g, 0.056 mmol) and a solution of the appropriate tri-n-butylstannane 6

	7.45-7.27 (m, 5H, H Ar ) , 4.77 (s, 2H, CH 2 Ph), 3.94 (s, 2H, CH 2 ). Other analyses were in
	accordance with the literature. 21
	(Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione (3a): To a suspension of TZD 2a (2.00
	g, 17.09 mmol) in AcOH (40 mL) were added β-alanine (1.82 g, 20.51 mmol) and 4-rinsed twice with cold MTBE, yielding 5 as a yellow powder (2.70 g, 7.91 mmol, 55%). M.p. (0.610 mmol) in DMF (2 mL). The reaction mixture was heated at 100 °C for 16 hours then
	methoxybenzaldehyde (2.33 g, 17.09 mmol). The reaction mixture was heated at 140 °C for 134-136 °C. IR (ATR): ν (cm -1 ) 3011, 1732, 1668, 1256. 1 H NMR (CDCl 3 , 400 MHz) δ 13.22 allowed to cool down at room temperature and was diluted with EtOAc (25 mL). A 1 M
	12 hours, allowed to come back to room temperature and filtered. The precipitate was washed (s, 1H, OH), 7.76-7.71 (m, 2H, H Ar ), 7.47-7.28 (m, 5H, H Ar ), 7.01-6.95 (m, 2H, H Ar ), 4.90 (s, aqueous solution of KF (20 mL) was added, the obtained biphasic mixture was vigorously
	with a water/AcOH 1/1 mixture (3 × 48 mL) and dried under vacuum to yield 3a as a yellow 2H, CH 2 ), 3.87 (s, 3H, CH 3 O). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 170.6 (C quat ), 168.1 stirred for 5 minutes and filtered over a Celite ® pad. The organic layer was washed with water
	powder (3.335 g, 14.18 mmol, 83%). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.70 (s, 1H, CH), (C quat ), 165.5 (C quat ), 162.6 (C quat ), 135.3 (C quat ), 129.9 (CH Ar ), 128.9 (CH Ar ), 128.8 (CH Ar ), (3 × 25 mL) and with an aqueous saturated solution of NaCl (25 mL), dried (MgSO 4 ) and the
	7.51 (d, 2H, J = 8.7 Hz, H Ar ),7.06 (d, 2H, J = 8.7 Hz, H Ar ), 3.81 (s, 3H, CH 3 ) Other analyses 128.3 (CH Ar ), 124.9 (C quat ), 114.4 (CH Ar ), 92.9 (C quat ), 55.6 (CH 3 ), 44.8 (CH 2 ). HRMS-ESI solvents were removed under reduced pressure. The afforded brown residue was dissolved
	were in accordance with the literature. 50 (pos. mode) m/z: [M+Na] + Calcd for C 18 H 15 NO 4 SNa 364.0614; Found 364.0644. with acetonitrile (CH 3 CN) (20 mL), washed with n-hexane (2 × 20 mL) and CH 3 CN was
	evaporated under reduced pressure.
	1 H NMR
	(CDCl 3 , 200 MHz) δ 7.86 (s, 1H, CH), 7.52-7.27 (m, 7H, H Ar ), 6.98 (d, J = 8.8 Hz, 2H, H Ar ), 3 , 400 MHz) δ 7.56-7.50
	4.90 (s, 2H, CH 2 ), 3.86 (s, 3H, CH 3 ). Other analyses were in accordance with the literature. 19 (m, 2x2H, H Ar ), 7.50-7.27 (m, 2x5H, H Ar ), 6.97-6.90 (m, 2x2H, H Ar ), 4.88 and 4.78 (2s,
	2x2H, CH 2 ), 3.86 (s, 2x3H, CH 3 O). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 166.5 (C quat ), 166.4
	(E)-3-Benzyl-5-(hydroxy(4-methoxyphenyl)methylene)thiazolidine-2,4-dione (5): To a (C quat ), 162.8 (C quat ), 161.8 (2 peaks, C quat ), 161.6 (C quat ), 143.6 (C quat ), 136.9 (C quat ), 135.2 (2
	solution of 2b (6.00 g, 28.95 mmol) in THF (60 mL) was added dropwise at -80 °C n-BuLi peaks, C quat ), 131.4 (CH Ar ), 130.2 (CH Ar ), 129.9 (C quat ), 129.2 (CH Ar ), 129.0 (CH Ar ), 128.8 (2
	(1.6 M in hexanes, 19.9 mL, 31.8 mmol). After stirring for 15 minutes, the reaction was peaks, CH Ar ), 128.4 (CH Ar ), 128.3 (CH Ar ), 127.2 (C quat ), 122.4 (C quat ), 119.7 (C quat ), 114.4
	H NMR (CDCl 3 , 400 MHz) δ

(Z)-3-Benzyl-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (3b):

To a solution of 3a (5.00 g, 21.

52 mmol)

in DMF (50 mL) were added Cs 2 CO 3 (7.69 g, 23.60 mmol) and BnBr (2.80 mL, 23.65 mmol). The reaction mixture was heated at 80 °C for 5 hours and then diluted with EtOAc (75 mL). The obtained precipitate was filtered and the filtrate was washed with water (3 × 50 mL). The organic layer was dried (MgSO 4 ) and the solvents were removed under vacuum. After evaporation, the yellow powder was suspended in a minimal amount of EtOAc and filtered to give 3b as a yellow powder (6.29 g, 19.35 mmol, 90%). allowed to warm to 0 °C over 1 hour, then cooled again at -80 °C. 4-Methoxybenzoyl chloride (5.87 mL, 43.3 mmol) was then added dropwise, while maintaining the temperature at -80 °C for 15 minutes.

(Z/E)-3-Benzyl-5-(chloro(4-methoxyphenyl)methylene)thiazolidine-2,4-dione (4c):

To a solution of 5 (2.19 g, 6.41 mmol) in POCl 3 (14.70 mL) was added DIPEA (1.90 mL, 10.91 mmol). The reaction mixture was heated at 110 °C for 6 hours, then POCl 3 was distilled off at 110 °C under reduced pressure. The obtained brown residue was diluted with EtOAc (150 mL), washed with water (3 × 100 mL) and with a saturated aqueous solution of NaCl (100 mL). The organic layer was dried (MgSO 4 ) and the solvents were removed under reduced pressure, yielding the (Z)-enriched 4c as a brown oil (2.28 g, 6.

35

mmol, 99%, (Z/E) ratio = 69/31). IR (ATR): ν (cm -1 ) 2837, 1736, 1676, 1256. 1 H NMR (CDCl (CH Ar ), 113.5 (CH Ar ), 55.6 (CH 3 ), 55.5 (CH 3 ), 45.3 (2 peaks, CH 2 ). HRMS-ESI (pos. mode) m/z: [M+Na] + Calcd for C 18 H 14 ClNO 3 SNa 382.0275; Found 382.0290.

General procedure for Stille cross-coupling:

  Bu 3 SnCl). HRMS-ESI (pos. mode) m/z: [M+Na] + Calcd for C 20 H 17 NO 3 SNa 374.0821; Found 374.0827. After CH 3 CN removal, the residue was purified by flash column Hz, 2H, H Ar ), 5.68 (td, J = 15.6 Hz, J = 5.7 Hz, 1H, CH=CHCH 2 ), 4.84 (s, 2H, CH 2 Ph), 4.66 (br s, 1H, NH), 3.93-3.86 (m, 2H, CH 2 NH), 3.85 (s, 3H, CH 3 O), 1.45 (s, 9H, t-Bu). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 167.9 (C quat ), 164.5 (C quat ), 160.4 (C quat ), 155.7 (C quat ), 149.0 [M+Na] + Calcd for C 26 H 28 N 2 O 5 SNa 503.1611; Found 503.1666.

	-1 ) 2926, 1732, 1668, 1246. 1 H NMR (CDCl 3 , 400 MHz) δ 8.24 (dd, J = 17.2 Hz, J = 10.6 Hz, 1H, CH=CH 2 ), 7.47-7.42 (m, 2H, H Ar ), 7.37-7.27 (m, 3H, H Ar ), 7.16 (d, J = 8.8 Hz, 2H, H Ar ), 6.95 (d, J = 8.8 Hz, 2H, H Ar ), 5.60 (dd, J = 10.6 Hz, J = 1.4 Hz, 1H, CH=CH cis H), 5.21 (dd, J = 17.2 Hz, J = 1.4 Hz, 1H, CH=CHH trans ), 4.85 (s, 2H, CH 2 ), 3.85 (s, 3H, OCH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 167.9 (C quat ), 164.5 (C quat ), 160.4 (C quat ), 149.8 (C quat ), 135.6 (C quat ), 134.3 (CH 2 =CH), 130.2 (CH Ar ), 129.6 (C quat ), 129.1 (CH Ar ), 128.8 (CH Ar ), 128.2 (CH Ar ), 126.3 (CH 2 =CH), 122.5 (C tert-Butyl ((2E,4Z)-4-(3-benzyl-2,4-dioxothiazolidin-5-ylidene)-4-(4-methoxyphenyl)but-2-en-1-yl)carbamate (1c): Preparation of tert-butyl (E)-(3-(tri-n-butylstannyl)allyl)carbamate (6a). 51 To a suspension of CuCN (0.58 g, 6.44 mmol) in THF (20 mL) was added dropwise n-BuLi (1.6 M in hexanes, 8.5 mL) at -80 °C. After stirring for 10 minutes, n-Bu 3 SnH (3.66 mL, 13.59 mmol) was added dropwise. After 15 minutes, a solution of N-Boc-propargylamine (1.00 g, 6.44 mmol) in THF (3 mL) was slowly added. After 2 hours at -80 °C, the reaction was quenched by the addition of a buffered NH 4 OH/NH chromatography in reverse phase (eluent: H 2 O/MeOH 50/50 to 10/90 in 20 minutes, then isocratic mode for 20 minutes). The expected derivative (Z)-1c (pure (Z)-isomer) was obtained as a yellow solid (0.056 g, 0.116 mmol, 21%). M.p. 83-85 °C. IR (ATR): ν (cm -1 ) (CH Ar ), 128.7 (CH=CH-CH 2 ), 128.2 (CH Ar ), 121.7 (C quat ), 114.4 (CH Ar ), 79.9 (C quat ), 55.5 3348, 2972, 1722, 1668, 1248. (C quat ), 140.3 (CH=CH-CH 2 ), 135.6 (C quat ), 130.1 (CH Ar ), 130.0 (C quat ), 129.0 (CH Ar ), 128.8 (CH 3 -O), 44.8 (CH 2 -Ph), 42.7 (CH 2 -NH), 28.5 (CH 3,t-Bu ). HRMS-ESI (pos. mode) m/z:

quat ), 114.3 (CH Ar ), 55.4 (CH 3 ), 44.8 (CH 2 ); (the NMR spectra showed slight excess of aliphatic signal, attributed to n-4 Cl solution (20 mL). The reaction mixture was diluted with EtOAc (50 mL), washed with water (3 × 30 mL) and with an aqueous saturated solution of NaCl. The organic layer was dried (MgSO 4 ) and the solvents were removed under reduced pressure.

After flash column chromatography (eluent: cyclohexane/EtOAc 100/0 for 20 minutes then to 95/5 in 20 minutes) 6a was afforded as a colourless oil (0.975 g, 2.18 mmol, 34%).

1

H NMR (CDCl 3 , 400 MHz): δ 0.85-0.91 (m, 15H, SnCH 2 , CH 3 ), 1.24-1.35 (m, 6H, CH 2 CH 3 ), 1.39-1.52 (m, 15H, CH 2 CH 2 CH 3 , t-Bu), 3.78 (br s, 2H, CH 2 NH), 4.59 (br s, 1H, NH), 5.92-6.00 (m, 1H, CH 2 -CH=CH), 6.05-6.12 (m, 1H, CH=CH). Other analyses were in accordance with the literature.

[START_REF] Bischoff | Stereoselective Construction of the 5-Hydroxy Diazabicyclo[4.3.1Decane-2-One Scaffold, a Privileged Motif for FK506-Binding Proteins[END_REF]

The compound 1c was prepared according to the general procedure for the Stille reaction with the tri-n-butylstannane 6a.

1

H NMR (CDCl 3 , 400 MHz) δ 8.09 (td, J = 15.6 Hz, J = 1.6 Hz, 1H, CH=CH-CH 2 ), 7.46-7.26 (m, 5H, H Ar ), 7.12 (d, J = 8.7 Hz, 2H, H Ar ), 6.94 (d, J = 8.7

  )-enriched isomer fraction of 1d (0.055 g, 0.11 mmol, 20%, (Z/E) ratio = 22/78 for (E)enriched 1d) and a pure mixture of the two stereoisomers (0.110 g, 0.22 mmol, 40%). for the pure mixture of isomers 1d: IR (ATR): ν (cm -1 ) 2930, 1728, 1676, 1236. HRMS-ESI (pos. mode) m/z: [M+H] + Calcd for C 27 H 26 NO 6 S 492.1475; Found 492.1464.

	Analysis Analysis for the (E)-enriched 1d: 1 H NMR (CDCl 3 , 400 MHz) δ 7.45-7.38 (2m, 2x2H, H Ar ),
	7.34-7.19 (2m, 2x5H, H Ar ), 6.92-6.87 (2m, 2x2H, H Ar ), 6.47 and 6.39 (2s, 2x2H, H Ar ), 4.82
	and 4.81 (2s, 2x2H, CH 2 ), 3.91 and 3.89 (2s, 2x3H, CH 3 ), 3.85 and 3.84 (2s, 2x3H, CH 3 ),
	3.77 and 3.74 (2s, 2x6H, CH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 168.4 (C quat ), 164.0
	(C quat ), 161.1 (C quat ), 160.8 (C quat ), 153.3 (C quat ), 152.9 (C quat ), 152.2 (C quat ), 151.8 (C quat ),
	139.1 (C quat ), 136.7 (C quat ), 135.8 (C quat ), 135.7 (C quat ), 134.4 (C quat ), 133.1 (C quat ), 131.9
	(CH Ar ), 131.3 (C quat ), 130.7 (C quat ), 129.2 (CH Ar ), 129.1 (CH Ar ), 128.7 (CH Ar ), 128.5 (CH Ar ),
	128.2 (CH
	1 H NMR (CDCl 3 , 400 MHz) δ 6.64 (s, 2H, H Ar ), 3.87 (s, 6H, CH 3 O), 3.85
	(s, 3H, CH 3 O), 1.60-1.51 (m, 6H, CH 2 ), 1.41-1.27 (m, 6H, CH 2 ), 1.12-0.98 (m, 6H, CH 2 ),
	0.90 (t, J = 7.2 Hz, 9H, CH 3 ). Other analyses were in accordance with the literature. 53
	The compound 1d was prepared according to the general procedure for the Stille reaction with
	the tri-n-butylstannane 6b. After purification of the crude product ((Z/E) ratio = 45/55) by

flash chromatography in reverse phase (eluent: H 2 O/MeOH 50/50 to 10/90 in 20 minutes, then isocratic mode for 20 minutes), 1d was isolated (yellow oil, 0.165 g, 0.33 mmol, 60%) as an (EAr ), 128.0 (CH Ar ), 122.4 (C quat ), 119.5 (C quat ), 114.2 (CH Ar ), 113.5 (CH Ar ), 107.5 (CH Ar ), 107.1 (CH Ar ), 61.1 (CH 3 ),

  1 H NMR (CDCl 3 , 400 MHz) δ 7.59-7.47 (m, 2H, H Ar ), 7.26-7.14 (m, 2H, H Ar ), 6.91 (d, J = 0.9 Hz, 1H, H furane ), 1.68-1.53 (m, 6H, CH 2 ), 1.44-1.29 (m, 6H, CH 2 ), 1.22-1.12 (m, 6H, CH 2 ), 0.91 (t, J = 7.2 Hz, 9H, CH 3

  HRMS-ESI (pos. mode) m/z: [M+Na] + Calcd for C 26 H 19 NO 4 SNa 464.0927; Found 464.1011. 1 H NMR (CDCl 3 , 400 MHz) δ 7.71-7.21 (m, 2x11H, H Ar , H benzofurane ), 7.04-6.94 (m, 2x2H, H Ar ), 6.57 (d, J = 0.9 Hz, 2x1H, H benzofurane ), 4.89 and 4.79 (2s, 2x2H, CH 2 ), 3.89 and 3.87 (2s, 2x3H, CH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 169.1 (C quat ), 164.5 (C quat ), 160.2 (C quat ), 156.2 (C quat ), 155.1 (C quat ), 136.7 (C quat ), 135.6 (C quat ), 130.6 (CH Ar ),

	14/86)
	by flash chromatography in reverse phase (eluent: H 2 O/MeOH 50/50 to 10/90 in 20 minutes,
	then isocratic mode for 20 minutes) 1e was obtained as an (E)-enriched isomer of 1e (yellow
	amorphous solid, 0.122 g, 0.28 mmol, (Z/E) ratio = 5/95, 50%). IR (ATR): ν (cm -1 ) 3030,
	1724, 1668, 1242. 129.0 (CH Ar ), 128.7 (CH Ar ), 128.3 (C quat ), 128.1 (CH Ar ), 127.9 (C quat ), 127.3 (CH Ar ), 124.0
	(CH Ar ), 122.3 (CH Ar ), 118.8 (C quat ), 115.6 (CH Ar ), 114.0 (CH Ar ), 111.9 (CH Ar ), 55.4 (CH 3 ),
	44.8 (CH 2 ).

  ESI (pos. mode) m/z: [M+Na] + Calcd for C 22 H 17 NO 3 S 2 Na 430.0542; Found 430.0579. J = 5.3 Hz, 1H, H pyridine ), 7.44-7.27 (m, 5H, H Ar ), 7.21-7.16 (m, 2H, H Ar ), 6.90-6.86 (m, 2H, H Ar ), 6.73 (dd, J = 5.3 Hz, J = 1.4 Hz, 1H, H pyridine ), 6.63 (br s, 1H, H pyridine ),4.81 (s, 2H, CH 2 ), 3.95 (s, 3H, CH 3 ), 3.84 (s, 3H, CH 3 ).13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ PrOH or t-BuOH) and toluene (3/2 v/v, 5 mL). After stirring for 1 minute, water (2 mL) and a 1 M aqueous solution of Na 2 CO 3 (832 µL, 0.832 mmol) were added. The reaction mixture was heated at 110 °C for 3 hours, allowed to cool down at rt and diluted with EtOAc

	HRMS-Analysis for the (Z)-enriched 1f: 1 H NMR (CDCl 3 , 400 MHz) δ 7.57 and 7.51 (2dd, J = 5.1 Hz, J = 1.1 Hz, 2x1H, H thiophene ), 7.47-7.14 (m, 2x8H, H thiophene , H Ar ), 7.10 and 7.05 (2dd, J = 3.9 Hz, J = 5.1 Hz, 2x1H, H thiophene ), 6.97-6.91 (m, 2x2H, H Ar ), 4.87 and 4.78 (2s, 2x2H, δ 8.20 (br d, 167.3 (C quat ), 164.7 (C quat ), 163.7 (C quat ), 160.9 (C quat ), 151.7 (C quat ), 148.6 (C quat ), 147.8
	CH 2 ), 3.87 and 3.86 (2s, 2x3H, CH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 167.7 (C quat ), (CH pyridine ), 135.4 (C quat ), 131.5 (CH Ar ), 129.5 (C quat ), 129.2 (CH Ar ), 128.8 (CH Ar ), 128.3
	164.2 (C quat ), 160.4 (C quat ), 144.4 (C quat ), 143.5 (C quat ), 135.6 (C quat ), 132.9 (CH Ar ), 131.6 (CH Ar ), 122.1 (C quat ), 116.3 (CH pyridine ), 113.7 (CH Ar ), 110.9 (CH pyridine ), 55.4 (CH 3 ), 54.0
	(CH Ar ), 131.4 (C quat ), 130.8 (2 peaks, CH Ar ), 129.2 (CH Ar ), 129.0 (CH Ar ), 128.8 (CH Ar ), 128.2 (CH 3 ), 45.2 (CH 2 ).
	(CH Ar ), 128.1 (CH Ar ), 113.8 (CH Ar ), 55.4 (CH 3 ), 45.1 (CH 2 ). General procedure for Suzuki cross-coupling: To a reaction medium of 4c (0.200 g, 0.555
	(Z/E)-3-Benzyl-5-((4-methoxyphenyl)(2-methoxypyridin-4-yl)methylene)thiazolidine-2,4-mmol) in toluene (4 mL) and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.023 g, 0.028 mmol) was added a
	dione (1g): This compound was prepared according to the general procedure for the Stille solution of the boronic acid derivative (0.832 mmol) in a mixture of the selected alcohol
	reaction with the commercially available 2-methoxy-4-(tri-n-butylstannyl)pyridine. After (EtOH, i-
	purification of the mixture ((Z/E) ratio = 58/42) of the two isomers of 1g by reverse phase
	flash column chromatography (eluent: water/MeOH 50/50 to 10/90 in 20 minutes, then
	isocratic mode for 10 minutes), the (E)-enriched isomer and the (Z)-enriched isomer were
	isolated as yellow oils (0.072 g, 0.166 mmol, 30%, (Z/E) ratio = 7/93 for (E)-enriched 1g and
	0.070 g, 0.161 mmol, 29%, (Z/E) ratio = 93/7 for (Z)-enriched 1g). Analysis for the mixture
	of isomers: IR (ATR): ν (cm-1) 2947, 1736, 1681, 1259. HRMS-ESI (pos. mode) m/z:
	[M+H] + Calcd for C 24 H 21 N 2 O 4 S 433.1217; Found 433.1254. Analysis for the (E)-enriched 1g:
	1 H NMR (CDCl 3 , 400 MHz) δ 8.20 (br d, J = 4.9 Hz, 1H, H pyridine ), 7.41-7.28 (m, 5H, H Ar ),
	48/52) was diluted with CH 3 CN to give an (Z)-enriched isomer fraction of 1f as 7.25-7.20 (m, 2H, H Ar ), 6.91-6.86 (m, 2H, H Ar ), 6.72 (br d, J = 4.9 Hz, 1H, H pyridine ), 6.58 (br
	a yellow precipitate (0.025 g, 0.06 mmol, 11%, Z/E ratio = 93/7). After evaporation of the s, 1H, H pyridine ), 4.78 (s, 2H, CH 2 ), 3.97 (s, 3H, CH 3 ), 3.83 (s, 3H, CH 3 ). 13 C{ 1 H} NMR
	filtrate, the residue was purified by flash chromatography in reverse phase (eluent: (CDCl 3 , 100.6 MHz) δ 167.8 (C quat ), 164.3 (C quat ), 163.8 (C quat ), 161.2 (C quat ), 150.6 (C quat ),
	H 2 O/MeOH 50/50 to 10/90 in 20 minutes, then isocratic mode for 20 minutes) to afford 1f as 147.5 (C quat ), 146.7 (CH pyridine ), 135.4 (C quat ), 131.4 (C quat ), 130.7 (CH Ar ), 129.1 (CH Ar ), 128.8
	a pure mixture of the two stereoisomers (yellow solid, 0.126 g, 0.31 mmol, 56%). Analysis for (CH Ar ), 128.3 (CH Ar ), 121.4 (C quat ), 117.1 (CH pyridine ), 114.5 (CH Ar ), 111.0 (CH pyridine ), 55.6
	the pure mixture of isomers 1f: M.p. 93-95 °C. IR (ATR): ν (cm -1 ) 2928, 1722, 1688, 1248. (CH 3 ), 53.9 (CH 3 ), 45.1 (CH 2 ). Analysis for the (Z)-enriched 1g: 1 H NMR (CDCl 3 , 400 MHz)

E)-3-Benzyl-5-((4-methoxyphenyl)(thiophen-3-yl)methylene)thiazolidine-2,4-dione (1k):

  Hz, 2x2H, H Ar ), 4.82 and 4.79 (2s, 2x2H, determined because of overlapping of signals in1 H NMR spectrum of the crude mixture) was done by flash column chromatography in reverse phase (eluent: water/MeOH 50/50 to 10/90 in 20 minutes then isocratic mode for 10 minutes), giving 1j as a pure mixture of the two This compound was prepared according to the general procedure for the Suzuki reaction CDCl 3 ) δ 6.58 (td, J 1 = 18.0 Hz, J 2 = 4.6 Hz, 1H, CH-CH 2 ), 5.57 (td, J 1 = 18.0 Hz,

	2x3H, CH 3 O). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 191.8 (CHO), 191.4 (CHO), 167.9 Preparation of tert-butyl (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate
	(C quat ), 167.4 (C quat ), 164.0 (C quat ), 163.7 (C quat ), 161.2 (C quat ), 160.9 (C quat ), 150.3 (C quat ), ((E)-8): The reaction mixture constituted of Schwartz reagent (zirconocene chloride hydride,
	149.4 (C quat ), 147.2 (C quat ), 145.8 (C quat ), 136.9 (C quat ), 136.3 (C quat ), 135.3 (2 peaks, C quat ), 0.165 g, 0.64 mmol), tert-butyl prop-2-yn-1-ylcarbamate (1.000 g, 4.50 mmol), pinacolborane
	132.1 (C quat ), 131.7 (CH Ar ), 131.0 (CH Ar ), 130.1 (CH Ar ), 130.0 (CH Ar ), 129.6 (CH Ar ), 129.2 stereoisomers (yellow oil, 0.063 g, 0.144 mmol, 26%, non-attributed ratio = 62/38). IR (1.40 mL, 9.66 mmol) and Et 3 N (0.10 mL, 0.64 mmol) was heated at 65 °C for 18 hours.
	(CH Ar ), 129.1 (CH Ar ), 128.8 (CH Ar ), 128.3 (CH Ar ), 121.9 (C quat ), 121.2 (C quat ), 114.4 (CH Ar ), (ATR): ν (cm -1 ) 2978, 1719, 1665, 1248. 1 H NMR (CDCl 3 , 400 MHz) δ 9.92 and 9.91 (2s, After dilution with EtOAc (25 mL) and hydrolysis with an aqueous saturated solution of
	113.7 (CH Ar ), 55.5 (CH 3 ), 55.4 (CH 3 ), 45.2 (CH 2 ), 45.0 (CH 2 ). HRMS-ESI (pos. mode) m/z: 2x1H, CHO), 7.73-7.69 (m, 2x1H, H thiophene ), 7.49-7.15 (m, 2x8H, H Ar , H thiophene ), 6.99-6.91 NH 4 Cl, the organic layer was washed with a NaHCO 3 5% aqueous solution (2 × 20 mL), a
	[M+Na] + Calcd for C 25 H 19 NO 4 SNa 452.0927; Found 452.0907. GC-MS (EI): 429 (36), 268 (m, 2x2H, H Ar ), 4.85 and 4.79 (2s, 2x2H, CH 2 ), 3.87 and 3.86 (2s, 2x3H, CH 3 ). 13 C{ 1 H} saturated NaCl aqueous solution (20 mL) and dried (MgSO 4 ). The solvents were removed
	(10), 152 (9), 91 (26). NMR (CDCl 3 , 100.6 MHz) δ 183.2 (CHO), 182.9 (CHO), 167.2 (C quat ), 166.6 (C quat ), 163.8 under reduced pressure. The crude residue was purified by flash column chromatography
	(C quat ), 163.6 (C quat ), 161.2 (C quat ), 160.7 (C quat ), 152.6 (C quat ), 149.3 (C quat ), 146.6 (C quat ), (eluant: cyclohexane/EtOAc 100/0 to 90/10 in 20 minutes then isocratic mode for 20 minutes)
	145.7 (C quat ), 141.9 (C quat ), 141.5 (C quat ), 135.5 (CH thiophene ), 135.3 (C quat ), 135.2 (C quat ), 135.2 to yield the pinacolborane (E)-8 as a colourless solid (0.835 g, 2.95 mmol, 46%). 1 H NMR
	(CH thiophene ), 132.7 (C quat ), 132.6 (CH thiophene ), 132.4 (CH thiophene ), 130.7 (CH Ar ), 130.5 (CH Ar ), (400 MHz,
	130.4 (C quat ), 129.2 (CH Ar ), 129.1 (CH Ar ), 128.9 (CH Ar ), 128.8 (CH Ar ), 128.4 (CH Ar ), 128.3
	(CH Ar ), 124.2 (C quat ), 121.4 (C quat ), 114.6 (CH Ar ), 114.1 (CH Ar ), 55.6 (CH 3 ), 55.4 (CH 3 ), 45.3
	CH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 168.5 (C quat ), 164.1 (C quat ), 162.9 (C quat ), 161.6 (CH 2 ), 45.2 (CH 2 ). HRMS-ESI (pos. mode) m/z: [M+H] + Calcd for C 23 H 18 NO 4 S 2 436.0672;
	(C quat ), 136.0 (C quat ), 131.0 (CH Ar ), 128.9 (CH Ar ), 128.7 (CH Ar ), 127.9 (CH Ar ), 122.6 (C quat ), Found 436.0790.
	114.1 (CH Ar ), 104.1 (C quat ), 66.8 (CH 2 O), 55.5 (CH 3 O), 44.6 (CH 2 Ph), 15.4 (CH 3 ). HRMS-ESI (pos. mode) m/z: [M+Na] + Calcd for C 20 H 19 NO 4 SNa 392.0927; Found 392.0929. (Z/E)-3-Benzyl-5-((4-methoxyphenyl)(phenyl)methylene)thiazolidine-2,4-dione (1a): This (Z/with the commercially available (thiophen-3-yl)boronic acid and EtOH as a co-solvent. After
	compound was prepared according to the general procedure for the Suzuki reaction with the the solvent removal, the organic residue ((Z/E) ratio = 50/50) was purified by flash
	commercially available phenylboronic acid and EtOH as a co-solvent. (Z/E) ratio of the crude chromatography on neutralized silica (silica neutralization: elution of cyclohexane + 1 %
	reaction mixture = 72/28. After purification by flash column chromatography in reverse phase Et 3 N, 200 mL, rinsed with a cyclohexane/EtOAc 80/20, 200 mL; purification eluent:
	(eluent: water/MeOH 50/50 to 10/90 in 20 minutes then isocratic mode for 10 minutes) 1a cyclohexane/EtOAc 100/0 to 93/7 in 20 minutes then isocratic mode for 20 minutes). The
	). IR (ATR): ν (cm -1 ) 2931, 1732, 1672, 1250. 1 H NMR was isolated as a pure mixture of the two stereoisomers as a yellow oil (0.169 g, 0.421 mmol, expected thienyl derivative 1k was isolated as a pure mixture of the two stereoisomers
	(CDCl 3 , 400 MHz) δ 10.05 and 10.04 (2s, 2x1H, CHO), 7.92-7.87 (m, 2x2H, H Ar ), 7.47-7.16
	(m, 2x9H, H Ar ), 6.92-6.87 (m, 2x2H, H Ar ), 4.83 and 4.78 (2s, 2x2H, CH 2 ), 3.84 and 3.83 (2s,

(E)-3-Benzyl-5-(ethoxy(4-methoxyphenyl)methylene)thiazolidine-2,4-dione (7a):

Yellow oil obtained as a by-product of functionalization using Suzuki cross-couplings within various yields (10-100%). IR (ATR): ν (cm -1 ) 2976, 1722, 1666, 1248.

1

H NMR (CDCl 3 , 400 MHz) δ 7.36 (d, J = 8.9 Hz, 2H, H Ar ), 7.37-7.27 (m, 5H, H Ar ), 6.99 (d, J = 8.9 Hz, 2H, H Ar ), 3.86 (s, 3H, CH 3 O), 4.74 (s, 2H, CH 2 Ph), 3.85 (q, J = 7.1 Hz, 2H, OCH 2 ), 1.23 (t, J = 7.1 Hz, 3H, 76%, (Z/E) ratio = 74/26). IR (ATR): ν (cm -1 ) 3055, 1730, 1670, 1248. 1 H NMR (CDCl 3 , 400 MHz) δ 7.44-7.17 (m, 2x12H, H Ar ), 6.88 (d, J = 8.9 (yellow solid, 0.065 g, 0.159 mmol, 29%, non-attributed ratio = 37/63). M.p. 69-71 °C. IR (ATR): ν (cm -1 ) 2833, 1726, 1668, 1246. 1 H NMR (CDCl 3 , 400 MHz) δ 7.46-7.01 (m, 2x10H, J 2 = 1.8 Hz, 1H, CH-B), 4.62 (br s, 1H, NH), 3.84 (m, 2H, CH 2 ), 1.44 (s, 9H, t-Bu), 1.26 (s, 12H, CH 3

). Other analyses were in accordance with the literature.

[START_REF] Lercher | DNA Modification under Mild Conditions by Suzuki-Miyaura Cross-Coupling for the Generation of Functional Probes[END_REF]

Methyl (2E,4Z)-4-(2,4-dioxothiazolidin-5-ylidene)-4-(4-methoxyphenyl)-2-methylbut-2- enoate (1p):

  1 H NMR (CDCl 3 , 400 MHz) δ 7.71-7.40 (m, 15H, H Ar ), 3.69 (br d, J = 26.2 Hz, 1H, CH), 2.09 (d, J = 1.8 Hz, 3H, CH 3 ). Other analyses were in accordance with the literature.[START_REF] Heckenbichler | Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases[END_REF] The compound 1o was prepared according the general procedure for the Wittig reaction starting from 11b. After purification by flash column chromatography (eluent: CH 2 Cl 2 /acetone 100/0 to 85/15 in 20 minutes), 1o was obtained as a yellow powder (0.064 g, 0.213 mmol, 56%). M.p. 193-195 °C. IR (ATR): ν (cm -1 ) 3125, 2992, 1732, 1695, 1252. 1 H NMR (CDCl 3 , 400 MHz) δ 8.87 (d, J = 16.1 Hz, 1H, CH=CHCO), 8.55 (br s, 1H, NH), 7.15 (d, J = 8.8 Hz, 2H, H Ar ), 6.98 (d, J = 8.8 Hz, 2H, H Ar ), 5.94 (d, J = 16.1 Hz, 1H, CH=CHCO), 3.86 (s, 3H, CH 3 O), 2.39 (s, 3H, CH 3 CO). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 199.5 (C quat ), 166.4 (C quat ), 164.8 (C quat ), 160.8 (C quat ), 147.2 (C quat ), 138.7 (CH), 136.7 (CH), 130.0 (CH Ar ), 129.2 (C quat ), 128.4 (C quat ), 114.8 (CH Ar ), 55.5 (CH 3 O), 27.2 (CH 3 CO). HRMS-ESI (neg. mode) m/z: [M-H] -Calcd for C 15 H 12 NO 4 S 302.0493; Found 302.0470.Preparation of methyl 2-(triphenylphosphanylidene)propanoate (11c):The phosphonium ylide 11c was prepared according the procedure described for 11b, starting from methyl 2bromopropionate (3.34 mL, 29.94 mmol) and was obtained as a white powder (1.45 g, 4.16 mmol, 86% in 2 steps).1 H NMR (CDCl 3 , 400 MHz): δ 1.57-1.62 (m, 3H, CH 3 ), 3.30 (br s, 3H, CH 3 O), 7.36-7.74 (m, 15H, H Ar ). Other analyses were in accordance with the literature.[START_REF] Werkhoven | Specific Isotope Enrichment of Methyl Methacrylate[END_REF] The compound 1p was prepared according the general procedure for the Wittig reaction starting from the phosphonium ylide 11c. After purification by flash column chromatography (eluent: CH 2 Cl 2 /acetone 100/0 to 95/5 in 20 minutes), 1p was obtained as a yellow oil (0.096 g, 0.289 mmol, 76%). IR (ATR): ν (cm -1 ) 3179, 2955, 1734, 1690, 1244.1 H NMR (CDCl 3 , 400 MHz) δ 8.34 (br s, 1H, NH), 8.16 (q, J = 1.6 Hz, 1H, CH), 7.30 (d, J = 9.1 Hz, 2H, H Ar ), 6.95 (d, J = 9.1 Hz, 2H, H Ar ), 3.86 (s, 3H, CH 3 O), 3.82 (s, 3H, CH 3 O), 1.45 (d, J = 1.6 Hz, 3H, CH 3 ). 13 C{ 1 H} NMR (CDCl 3 , 100.6 MHz) δ 168.5 (C quat ), 167.0 (C quat ), 164.5 (C quat ), 161.1 (C quat ), 146.4 (C quat ), 136.3 (CH), 134.8 (C quat ), 131.0 (C quat ), 130.2 (CH Ar ), 124.7 (C quat ), 114.8 (CH Ar ), 55.5 (CH 3 O), 52.6 (CH 3 O), 15.1 (CH 3 ). HRMS-ESI (neg. mode) m/z: [M-H] -Calcd for C 16 H 14 NO 5 S 332.0598; Found 332.0591.Preparation of (triphenylphosphanylidene)acetonitrile (11d):The phosphonium ylide 11d was prepared according the described procedure for 11b, starting from the commercially available (cyanomethyl)triphenylphosphonium chloride (2.00 g, 5.92 mmol). The phosphonium ylide 11d was obtained as a white powder (1.62 g, 4.66 mmol, 91%).1 H NMR (CDCl 3 , 400 MHz) δ 7.71-7.43 (m, 15H, H Ar ), 1.62-1.57 (m, 1H, CH). Other analyses were in accordance with the literature.[START_REF] Bestmann | Synthese von Nitrilen Über Das Ylidanion von Natriumcyantriphenylphosphoranylidenmethanid[END_REF] The compound 1q was prepared according the general procedure for the Wittig reaction starting from the phosphonium ylide 11d. After purification by flash column chromatography (eluent: CH 2 Cl 2 /acetone 100/0 to 95/5 in 20 minutes) 1q was obtained as a yellow oil (0.066 g, 0.231 mmol, 61%). IR (ATR): ν (cm -1 ) 3175, 3071, 2216, 1738, 1693, 1244.1 H NMR (acetone-d 6 , 400 MHz) δ 11.18 (br s, 1H, NH), 8.84 (d, J = 16.4 Hz, 1H, CH=CHCN), 7.30 (d, J = 8.8 Hz, 2H, H Ar ), 7.10 (d, J = 8.8 Hz, 2H, H Ar ), 5.44 (d, J = 16.4 Hz, 1H, CHCN), 3.88 (s, 3H, CH 3 ). 13 C{ 1 H} NMR (acetone-d 6 , 100.6 MHz) δ 166.5 (C quat ), 166.1 (C quat ), 161.8 (C quat ), 145.9 (CH), 143.9 (C quat ), 131.9 (C quat ), 131.0 (CH Ar ), 128.4 (C quat ), 118.6 (C quat ), 115.6 (CH Ar ), 106.1 (CH), 55.8 (CH 3 ). HRMS-ESI (neg. mode) m/z: [M-H] -Calcd for C 14 H 9 N 2 O 3 S 285.0339; Found 285.0331.

	(2E,4Z)-4-(2,4-Dioxothiazolidin-5-ylidene)-4-(4-methoxyphenyl)but-2-enenitrile	(1q):

Acknowledgments

We gratefully acknowledge CNRS, Université de Lorraine for financial support and MENRT for a fellowship to Dorian Dupommier. For technical support and recording spectra, the authors thank sincerely S. Adach and F. Lachaud from SynBioN (Université de Lorraine-CNRS-http://synbion.univ-lorraine.fr/accueil/), F. Dupire from the mass spectrometry MassLor platform -Université de Lorraine as well as the technical staff of the platform RMN de l'Institut Jean Barriol (Université de Lorraine). Computational resources were partially provided by the Mésocentre EXPLOR of the Université de Lorraine.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

CH 2 ), 3.84 and 3.83 (2s, 2x3H, CH 3 ). 13

(Z/E)-5-((3-Benzyl-2,4-dioxothiazolidin-5-ylidene)(4-methoxyphenyl)methyl)thiophene-

2-carbaldehyde (1j):

This compound was prepared according to the general procedure for the Suzuki reaction with the commercially available (5-formylthiophen-2-yl)boronic acid and EtOH as a co-solvent. The purification of the crude reaction mixture ((Z/E) ratio was not

General procedure for the Wittig reaction:

To a solution of the aldehyde 10 (0.100 g, 0.380 mmol) in THF (10 mL) was added the selected phosphonium ylide 11b-d (0.836 mmol). The reaction mixture was stirred at rt for 15 hours. THF was then removed under reduced pressure.

Methyl (2E,4Z)-4-(2,4-dioxothiazolidin-5-ylidene)-4-(4-methoxyphenyl)but-2-enoate

(Z)-5-((E)-1-(4-Methoxyphenyl)-4-oxopent-2-en-1-ylidene)thiazolidine-2,4-dione (1o):

Preparation of (triphenylphosphanylidene)propan-2-one (11b): To a solution of PPh 3 (7.17 g, 27. 35 mmol) in EtOAc (30 mL) was added 2-chloroacetone (2.00 mL, 24.86 mmol). The reaction mixture was refluxed at 90 °C for 3 hours and the formed precipitate was filtered, washed with EtOAc (2 × 10 mL) and dried under vacuum to give the chlorophosphonium salt as a white powder (5.82 g, 16.40 mmol, 60 %). The latter compound (2.00 g, 5.63 mmol) was

Supporting Information

X-ray data for 5 and 9; NMR study of the tautomeric equilibrium between 5 and 5';

Benzylidene double-bond assignment using the combined theorical calculation/NMR studies for 1a-q and 4c; Comparison of the


Christine Barret-Grimault

Marie-Claire Ombret

Owen Kevin Appadoo

Hugo Rositi

Sylvie Valarier

Eloïse Privat

Inès Benmabrouk

Victoria Haas

Vanessa Rousset

Stéphanie Verret

Innovons en ETP grâce au casque HoloLens en chirurgie bariatrique !

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Christine BARRET-GRIMAULT 1 , Marie-Claire OMBRET 1 , Owen APPADOO 2 , Hugo ROSITI 2 , Sylvie VALARIER 1 , Eloïse PRIVAT 1 , Inès BENMABROUK 1 , Victoria HAAS 1 ,Vanessa ROUSSET 3 , Stéphanie VERRET 1 , Christophe LOHOU 2 , Emilie GADEA 1 .

CH Emile Roux (Le Puy-en-Velay) 1 , IUT: département Informatique -Informatique Graphique (Université Clermont Auvergne, le Puy en Velay) 2 , Centre HYGEE (Saint-Priest-en-Jarez)

  d'éducation thérapeutique (ETP) de chirurgie bariatrique (CB), il a été constaté que les patients avaient des difficultés à prendre conscience de l'importance de la réduction gastrique et des adaptations alimentaires à effectuer, malgré l'utilisation de méthodes pédagogiques standard. OBJECTIF L'objectif de l'étude est de tester la faisabilité et l'acceptabilité de la réalité mixte (RM) dans une séance d'ETP qui a pour but de visualiser les changements occasionnés par la CB. MATÉRIEL ET MÉTHODE Lors d'un atelier nutrition, un casque Microsoft HoloLens® (RM) proposé en France depuis fin 2016, a été utilisé chez un groupe de 30 patients. Une application permet au patient de visualiser la réduction gastrique (Sleeve ou Bypass au choix). Un self virtuel propose au patient de composer un menu équilibré, en respectant les capacités gastriques. Un questionnaire de satisfaction a été utilisé, accompagné du questionnaire SUS (System Usuability Scale). Oui tout à fait Non pas vraiment/Non pas du tout L'application permet-elle une meilleure représentation des quantités et du type d'aliments à consommer ?

pédagogiques Innovons en ETP grâce au casque HoloLens® en chirurgie bariatrique! SCORE moyen et médiane SUS = 70% [min 35; max 100]

	POPULATION OBSERVÉE
			Sexe	n=30
	Homme	3	(10%)
	Femme			27	(90%)
					n=30
	RÉSULTATS : Score d'utilisabilité
	au SUS (adaptée de Bangor et al., 2008) RÉSULTATS : Aspects Échelle d'interprétation du score total	CONCLUSION ET
					RÉSULTATS : Aspects	PERSPECTIVES L'utilisation de la RM avec le
					technologiques	casque HoloLens® en ETP est faisable et globalement
					appréciée par les patients.
					Cependant l'utilisation de
					cette technologie nécessite
					une assistance technique
					aussi bien pour les patients
					que pour les éducateurs. Un
					travail	important	de
					développement et de mise
					en service de l'application
					reste à faire pour qu'elle soit
					utilisable	en	pratique
					courante. En attendant, un
					(50%)	outil	pédagogique	sur
					(50%)	tablette de type Serious Game semble être plus
					facilement accessible pour
					les patients et les soignants
					(actuellement en cours de
					(60%)	développement). L'efficacité
					(40%)	pédagogique de ces outils restent à investiguer.

« A16275EG » (PC-1) Financement : PEPS CNRS INSIS « Sciences de l'Ingénierie pour la Santé pour accompagner des projets translationnels », 2017, projet AVACM 15 15 Oui Non Nécessité d'une assistance technique? (23%) 12 18 Oui Non Préférence pour l'utilisation d'un ordinateur ou tablette à la place du casque ?