Photoswitchable interlocked thiodiglycolamide as a cocatalyst of a chalcogeno-Baylis–Hillman reaction

The sulfur-based template of light-driven molecular shuttles is able to modulate its catalytic activity in a diastereoselective chalcogeno-Baylis–Hillman reaction.


General Experimental Section
Unless stated otherwise, all reagents were purchased from Aldrich Chemicals and used without further purification. HPLC grade solvents (Scharlab) were nitrogen saturated and were dried and deoxygenated using an Innovative Technology Inc. Pure-Solv 400 Solvent Purification System. Column chromatography was carried out using silica gel (60 Å, 70-200 m, SDS) as stationary phase, and TLC was performed on precoated silica gel on aluminun cards (0.25 mm thick, with fluorescent indicator 254 nm, Fluka) and observed under UV light. All melting points were determined on a Kofler hot-plate melting point apparatus and are uncorrected. 1 H-and 13 C-NMR spectra were recorded at 298 K on a Bruker Avance 300 and 400 MHz instruments. 1 H NMR chemical shifts are reported relative to Me 4 Si and were referenced via residual proton resonances of the corresponding deuterated solvent whereas 13 C NMR spectra are reported relative to Me 4 Si using the carbon signals of the deuterated solvent. Signals in the 1 H and 13 C NMR spectra of the synthesized compounds were assigned with the aid of DEPT, APT, or two-dimensional NMR experiments (COSY, HMQC and HMBC). Abbreviations of coupling patterns are as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet. Coupling constants (J) are expressed in Hz. High-resolution mass spectra (HRMS) were obtained using a time-of-flight (TOF) instrument equipped with electrospray ionization (ESI).. To a suspension of 2,2'-thiodiacetic acid 1 (1.5 g, 10.0 mmol) in dry dichloromethane (40 mL) under N 2 atmosphere was added oxalyl chloride (3.81 g, 30.0 mmol) and DMF (4 drops). The mixture was stirred for 3 hours under reflux. After this time the solvent and the excess of oxalyl chloride were removed under reduced pressure. The resulting residue was used in the next step without purification.
To a solution of 2,2-diphenylethanamine (2.30 g, 11.7 mmol) and Et 3 N (2.25 mL, 16.0 mmol) in CHCl 3 (60 mL) was added dropwise the residue obtained in the previous step (1.00 g, 5.35 mmol), dissolved in 10 mL of CHCl 3 , during a period of 1 hour. After stirring at room temperature for another hour, the reaction was refluxed for 3 hours. The reaction mixture was washed with water (2 x 100 mL), HCl 1N (2 x 100 mL), NaOH 1N (2 x 100 mL) and brine (2 x 100 mL). The organic phase was dried over anhydrous To a suspension of 2,2'-thiodiacetic acid 1 (1.5 g, 10.0 mmol) in dry dichloromethane (40 mL) under N 2 atmosphere was added oxalyl chloride (3.81 g, 30.0 mmol) and DMF (4 drops). The mixture was stirred S5 for 3 hours under reflux. After this time the solvent and the excess of oxalyl chloride were removed under reduced pressure. The resulting residue was used in the next step without purification.

S6
Fragment S2a was synthesized following the described procedure reported in A. Martinez-Cuezva, S.
After this time EDCI (0.96 g, 5.0 mmol) was added and the reaction was stirred at room temperature for 48 hours. The reaction mixture was washed with water (2 x 100 mL), HCl 1N (2 x 100 mL), NaOH 1N (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a To a solution of fragment 6b (2.4 g, 3.9 mmol) in dry CH 2 Cl 2 (50 mL) was added TFA (1.50 mL, 19.5 mmol) and was stirred at room temperature for 12 hours. After this time the solvent and excess of TFA were removed under reduced pressure. The resulting residue was dissolved in CH 2 Cl 2 :MeOH (1:1) (50 mL) and basic resin Amberlyst® A-21 (1 g) was added. The mixture was stirred for 1 hour. After this time the solution was filtered and the solvent was removed under reduced pressure. The corresponding residue was employed in the next step without further purification.
To a solution of the resulting free amine (0.95 g, 1.85 mmol) in dry CH 2 Cl 2 (35 mL) was added acid S2 (545 mg, 1.85 mmol) and DMAP (225 mg, 1.85 mmol). The solution was stirred at 0ºC during 15 min and EDCI (355 mg, 1.85 mmol) was added. The reaction was stirred at room temperature for 48 hours.
After this time the mixture was diluted with CH 2 Cl 2 (50 mL) and was washed with water (2 x 100 mL), HCl 1N (2 x 100 mL), NaOH 1N (2 x 100 mL) and brine (2 x 100 mL). The organic phase was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a CH 2 Cl 2 /MeOH (40/1) mixture as eluent to give the title product as yellow oil (E-7b, 956
To a solution of fragment 6a (3.00 g, 3.23 mmol) in dry CH 2 Cl 2 (40 mL) was added TFA (2.34 mL, 32.3 mmol) and was stirred at room temperature for 12 hours. After this time the solvent and excess of TFA were removed under reduced pressure. The resulting residue was dissolved in EtOH (30 mL) and S11 Amberlyst ® A21 (3 g) was added. The mixture was stirred at room temperature for 1 hour. The resin was filtered and the solvent was removed under reduced pressure, to give the unprotected amine, which was used in the next step without further purification.
To a suspension of acid S3a (0.952 g, 3.23 mmol) in dry CH 2 Cl 2 (40 mL) under N 2 atmosphere was added unprotected amine (1.00 g, 3.32 mmol), Et 3 N (0.7 mL, 5.09 mmol) and BOP (2.25 g, 5.09 mmol) and the reaction mixture was stirred at room temperature for 5 hours. After this time the reaction mixture was diluted with CH 2 Cl 2 (60 mL) and washed with water (2 x 100 mL), HCl 1N (2 x 100 mL), NaOH 1N (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The resulting residue was extensively washed with Et 2 O, giving the title product as a white solid

S12
To a solution of the resulting free amine (0.95 g, 1.85 mmol) in dry CH 2 Cl 2 (35 mL) was added acid S3b (545 mg, 1.85 mmol) and BOP (817 mg, 2.22 mmol). The reaction was stirred at room temperature for 5 hours. After this time the mixture was diluted with CH 2 Cl 2 (50 mL) and was washed with water (2 x 100 mL), HCl 1N (2 x 100 mL), NaOH 1N (2 x 100 mL) and brine (2 x 100 mL). The organic phase was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a CH 2 Cl 2 /MeOH (80/1) mixture as eluent to give the title

General procedure for the preparation of the [2]rotaxanes 3 and E-8
The thread (1 equiv.) and Et 3 N (24 equiv.) in anhydrous CHCl 3 (250 mL) were stirred vigorously whilst solutions of p-xylylenediamine (8 equiv.) in anhydrous CHCl 3 (20 mL) and isophthaloyl chloride (8 equiv.) in anhydrous CHCl 3 (20 mL) were simultaneously added over a period of 4 h using motor-driven syringe pumps. After a further 4 h the resulting suspension was filtered through a Celite ® pad, washed with water (2 x 50 mL), an aqueous solution of HCl 1N (2 x 50 mL), a saturated solution of NaHCO 3 (2 x 50 mL) and brine (2 x 50 mL). The organic phase was dried over MgSO 4 and the solvent removed under reduced pressure. The resulting solid was subjected to column chromatography (silica gel) to yield unconsumed thread and [2]rotaxane.

Chalcogenide-TiCl 4 catalyzed Baylis-Hillman reaction
Reaction conditions for this transformation reported in S. Kinoshita, H. Kinoshita, T. Iwamura, S.-I. Watanabe, T. Kataoka, Chem.-Eur. J. 2003, 9, 1496-1502 General procedure: To a solution of p-nitrobenzaldehyde (3.8 mg, 0.025 mmol), 3-butyn-2-one (5.1 mg, 0.075 mmol) and the corresponding sulfide derivative "S" (0.1 equiv.) in dry CH 2 Cl 2 at 0-5ºC was added TiCl 4 (0.025 mmol, solution 1M in CH 2 Cl 2 ). The reaction was stirred under nitrogen at the established temperature for 3 hours. After this time a saturated solution of NaHCO 3 (0.5 mL) was added. The reaction mixture was diluted with CH 2 Cl 2 and extracted with H 2 O. The organic phase was dried over MgSO 4 and the solvent removed under reduced pressure. The corresponding residue was analyzed by 1 H NMR spectroscopy and the conversion and diastereomeric ratio of E-9 and Z-9 was calculated. Table S1. Screening of the reaction conditions for the BH transformation of p-nitrobenzaldehyde and 3-butyn-2-one.    Figure S2. Molecular structure of rotaxane 3a with thermal ellipsoids drawn at 50% probability.

X-ray Structure Determinations.
A colorless prism-like specimen of C 67 H 66 N 6 O 7 S, approximate dimensions 0.040 mm x 0.170 mm x 0.220 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured on a Bruker D8 QUEST system equipped with a multilayer monochromator and a Cu K/a Incoatec microfocus sealed tube (λ = 1.54178 Å).
A total of 2452 frames were collected. The total exposure time was 81.73 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 88755 reflections to a maximum θ angle of 66.67° (0.84 Å resolution), of which 9949 were independent (average redundancy 8.921, completeness = 97.5%, R int = 3.63%, R sig = 1.77%) and 8893 (89.39%) were greater than 2σ(F 2 ). The final cell constants of a = 10.2417 (8)  S21 volume = 2885.6(4) Å 3 , are based upon the refinement of the XYZ-centroids of 9037 reflections above 20 σ(I) with 5.699° < 2θ < 133.3°. Data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.880. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.8116 and 0.9615.
The final anisotropic full-matrix least-squares refinement on F 2 with 735 variables converged at R1 = 4.46%, for the observed data and wR2 = 14.77% for all data. The goodness-of-fit was 1.175. The largest peak in the final difference electron density synthesis was 0.565 e -/Å 3 and the largest hole was -0.299 e -/Å 3 with an RMS deviation of 0.066 e -/Å 3 . On the basis of the final model, the calculated density was 1.263 g/cm 3 and F(000), 1158 e -.  (3) 118 (2) Symmetry transformations used to generate equivalent atoms: #1 -x+2,-y+1,-z+1 #2 -x+1,-y,-z #3 -x+1,-y+1,-z+1 A CH··· interaction between one of the methylenic hydrogen atoms of the thread and one of the pxylylene rings of the tetralactam is observed. This interaction is featured by a distance of 3.4 Å between the C41 and the centroid (CD1) and angle of 86º between the C41-H41A bond and the nearest carbon of the centroid ( Figure S3).