Experimental section

All reagents, metal catalysts and solvents were obtained from commercial sources and were purified before use by standard methods.^[158] All experiments requiring dry atmosphere were carried out under nitrogen atmosphere using standard Schlenk technique. Silica gel 60 (40–63 μm) for flash chromatography was purchased from Macherey & Nagel (Düren). NMR spectra were measured on JEOL Eclipse-ECP 400 and Bruker Avance DRX 600 spectrometers. ¹H NMR chemical shifts are referenced with respect to the chemical shift of the residual protons present in the deuterated solvents (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm; DMSO: δH = 2.50 ppm, δC = 39.52 ppm; [D6]-Acetone: δH = 2.05 ppm, δC = 29.84, 206.26 ppm). UV-vis spectra were recorded on a Varian Cary 50 spectrophotometer and a Perkin Elmer Lambda 18 (200-600 nm) in dilute (~10^-5 M) THF solutions.

IR spectra were recorded on a Perkin Elmer Spectrum 100 FTIR (ATR) spectrometer. Melting points are not corrected and were measured with a Krüss-Meltingpointmeter KFP I N. High resolution mass spectra were recorded of 1 μM dilute samples in acetonitrile-acetone-water-solutions on a Bruker micrOTOF II mass spectrometer. Elemental analyses were carried out in the micro analytical lab of the University of Konstanz using an Elementar Vario EL CHN analyzer.

X-ray Crystallography. Suitable single crystals of 7d and 7e were grown by slow diffusion of hexane into a saturated solution of 7d in acetone or of hexane into a saturated solution of 7e in dichloromethane. Crystal were directly picked from solution and covered in an inert oil and immediately placed in the cold N2-stream of the Oxford Cryostream 700 with nitrogen as coolant gas.

Data collection for X-ray structure-determination was performed at a STOE IPDS-II diffractometer equipped with a graphite monochromated radiation source (λ = 0.71073 Å), an image plate detection system. The selection, integration, and averaging procedure of the measured reflex intensities, the determination of the unit cell by a least-squares fit of the 2Θ values, data reduction, LP correction, and the space group determination were performed using the X-Area software package delivered with the diffractometer. A semiempirical absorption correction method was performed after indexing of the crystal faces. The structure was solved by direct methods (SHELXS-97)^[159] and refined by standard Fourier techniques against F square with a full-matrix leastsquares algorithm using SHELXL-97 and the WinGX (1.80.05)^[160] software package. All non hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in calculated positions and refined with a riding model.

Graphical representations were prepared with ORTEP-III.^[161] Crystallographic data (excluding structure factors) of 7d and 7e have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 1031337 and 1410575. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, U.K. (fax:

(+44)1223−336−033. e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).

Cytotoxicity assay. Cytotoxicity was measured on HeLa S3 and Hep G2 cells using an AlamarBlue (Thermo Scientific) assay.^[162] Alamarblue was purchased from BioSource Europe. Cells were cultivated at 37 °C in humidified 5% CO2 atmosphere using Dulbecco’s DMEM-media (Invitrogen) containing 10 % foetal calf serum (Biochrome AG), 1 % penicillin and 1 % streptomycin (both GIBCO). Cells were split twice per week. Both cell lines were tested on mycoplasma infections using a mycoplasma detection kit (Roche Applied Science). The cells were seeded in 96-well plates (4.000 HeLa S3 cells/well or 8.000 Hep G2 cells/well) and allowed to attach for 24 h. The cells were then incubated with different concentrations of the reagent to be tested. Compounds to be tested were dissolved in a suitable amount of DMSO and different concentrations were prepared by serial dilution with DMSO. One part of each DMSO solution is then added to 99 parts of medium. Cells were then incubated for 48 h with 100 μl of above medium containing 1% DMSO and a certain concentration of compound. The medium was then replaced by 100 μL medium containing 10 % AlamarBlue (BioSource Europe) and the cells were incubated for 90 min. The fluorescence at 590 nm was measured after excitation at 530 nm using a Synergy HT Microplate Reader (BioTek). Raw readout data from the assay was corrected for background fluorescens by an “onplate” blind containing only medium, 1 % DMSO and Alamarblue but no cells (0-value). The background

corrected absolute read-outs were then expressed as relative values with regard to an “on-plate” 100 % standard containing untreated cells in medium with 1 % DMSO. All data was then fitted to a sigmoidal dose-response model with variable slope (4 parameter logistic nonlinear regression model) using Sigma plot 10.0.^[163] Upper and lower boundaries as well as the slope were allowed to refine freely.

All experiments were repeated at least three times on three different days with each experiment done in four replicates on the same plate. Replicates are treated with equal statistical weight; Error-bars representing SEM. IC50 values are given as means from independent experiments, error values of IC50

are based on standard deviation of independent experiments.

3-formyl-4-hydroxybenzene-1-sulfonyl chloride (2): Chlorosulfonic acid (147.7 g, 1.27 mol) was added slowly to 2-((phenylimino)methyl)phenol 1 (25 g, 126.7 mmol) at 0 ^oC under stirring. The reaction was allowed to proceed for 20 h at r.t. The reaction mixture wa s then added portionwise to ice (1000 g) and extracted with CH2Cl2 (3 × 100 mL). The combined organic phase was washed three times with aqueous 50 % H2SO4 solution (100 ml). The organic layer was dried over Na2SO4, and the solvent was evaporated in vacuo to give 2 as a yellow solid (19.4 g, 87.93 mmol, 70 %). M.p. 121-122 ^oC; IR absorptions (cm^-1, ATR): 1682, 1665, 1567, 1468, 1379, 1291, 1174, 1078, 709; ¹H NMR (CDCl3, 400 MHz): δ 11.71 (s, 1H, OH), 10.00 (s, 1H, HC=O), 8.32 (s, 1H, Har), 8.15 (d, J = 6.4 Hz, 1H, Har), 7.22 (d, J = 6.4 Hz, 1H, Har); ¹³C NMR (CDCl3, 101 MHz): δ 195.4 (C=O), 166.6 (Car), 135.9 (Car), 134.9 (Car), 133.8 (Car), 120.0 (Car); HRMS (ESI-TOF) m/z Calcd for C7H6ClO4S [M+H]

+ : 220.9670. Found: 220.9672.

2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzaldehyde (4a): To a solution of 2 (3.0 g, 13.5 mmol) in 40 ml CH2Cl2 was added portionwise pyrrolidine (1.19 g, 16.7 mmol) at 0 ^oC, the reaction was allowed to proceed for another 12 h and warm to r.t., the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/Petroleum ether = 2:1) to give 4a as a yellow solid (2.85 g, 11.16 mmol, 83 %). M.p. 158-159 ^oC; IR absorptions (cm^-1, ATR): 2981, 2878, 1642, 1617, 1469, 1320, 1191, 1088, 751; ¹H NMR (CDCl3, 400 MHz): δ 11.37 (s, 1H, OH), 9.95 (s, 1H, HC=O), 8.10 (d, J = 2.4 Hz, 1H, Har), 7.92 (dd, J = 2.4, 8.8 Hz, 1H, Har), 7.09 (d, J = 8.8 Hz, 1H, Har), 3.24-3.20 (m, 4H, NCH2), 1.78-1.76 (m, 4H, NCH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 196.1 (C=O), 164.5 (Car), 135.4 (Car), 133.8 (Car), 129.0 (Car), 119.9 (Car), 118.9 (Car), 48.1 (NCH2), 25.3 (NCH2CH2); ESI-MS m/z (%): 256 (90) [(M+H)⁺]; Anal. Calcd. for C11H13NO4S: C, 51.75; H, 5.13;

N, 5.49. Found: C, 51.78; H, 5.28; N, 5.55.

2-hydroxy-5-(piperidin-1-ylsulfonyl)benzaldehyde (4b): Following the same procedure as for compound 4a with 2 (3.0 g, 13.5 mol), piperidine (5.78 g, 67.9 mmol) in 50 ml CH2Cl2 for 1 h to give 4b as a yellow solid (3.18 g, 11.8 mmol, 87 %). M.p. 168-170 ^oC; IR absorptions (cm^-1, ATR): 2927, 1662, 1292, 1154, 925, 742; ¹H NMR (CDCl3, 400 MHz): δ 11.40 (s, 1H, OH), 9.96 (s, 1H, HC=O), 8.03 (d, J = 2.4 Hz, 1H, Har), 7.87 (dd, J = 2.4, 8.8 Hz, 1H, Har), 7.12 (d, J = 8.8 Hz, 1H, Har), 3.01 (t, J = 4.0 Hz, 4H, NCH2), 1.68-1.63 (m, 4H, NCH2CH2), 1.47-1.41 (m, 2H, NCH2CH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 196.0 (C=O), 164.7 (Car), 135.6 (Car), 134.0 (Car), 128.4 (Car), 120.0(Car), 118.9 (Car), 47.1 (NCH2), 25.3 (NCH2CH2), 23.6 (NCH2CH2CH2); ESI-MS m/z (%): 270 (100) [(M+H)⁺];

Anal. Calcd. for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.61; H, 5.45; N, 5.34.

5-(azepan-1-ylsulfonyl)-2-hydroxybenzaldehyde (4c): Following the same procedure as for 4a with 2 (3.19 g, 14.4 mmol), azepane (2.85 g, 28.7 mmol) in 25 ml CH2Cl2 for 2.5 h to give 4c as a light yellow solid (1.35 g, 4.7 mmol, 33 %); M.p. 152-154 ^oC; IR absorptions (cm^-1, ATR): 2915, 1661, 1321, 1086, 997, 875, 736; ¹H NMR (CDCl3, 400 MHz): δ 11.37 (s, 1H, OH), 9.95 (s, 1H, HC=O), 8.08 (d, J = 2.4 Hz, 1H, Har), 7.90 (dd, J = 2.4, 8.8 Hz, 1H, Har), 7.10 (d, J = 8.8 Hz, 1H, Har), 3.29 (t, J = 4.0 Hz, 4H, NCH2), 1.74-1.72 (m, 4H, NCH2CH2), 1.62-1.59 (m, 4H, NCH2CH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 196.0 (C=O), 164.4 (Car), 135.0 (Car), 133.3 (Car), 131.7 (Car), 120.0 (Car), 119.0 (Car), 48.4 (NCH2), 29.3 (NCH2CH2), 27.1(NCH2CH2CH2); HRMS (ESI-TOF) m/z Calcd for C13H18NO4S [M+H]⁺ : 284.0951. Found: 284.0959.

2-hydroxy-5-(morpholinosulfonyl)benzaldehyde (4d): Following the same procedure as for 4a with 2 (5.0 g, 22.7 mmol), morpholin (20.18 g, 231.7 mmol) in 50 ml CH2Cl2 for 2.5 h to give 4d as

a light yellow solid (5.37 g, 19.79 mmol, 88 %); M.p. 187-188 ^oC; IR absorptions (cm^-1, ATR): 2993, 1685, 1668, 1348, 1328, 1260, 1225, 1150, 1111, 941,742; ¹H NMR (d6-DMSO, 400 MHz): δ 11.85 (s, 1H, OH), 10.32 (s, 1H, HC=O), 7.93 (d, J = 2.0 Hz, 1H, Har), 7.81 (dd, J = 2.0, 8.8 Hz, 1H, Har), 7.22 (d, J = 8.8 Hz, 1H, Har), 3.7 (t, J = 4.0 Hz, 4H, OCH2), 2.85 (t, J = 4.0 Hz, 4H, NCH2); ¹³C NMR (d6-DMSO, 101 MHz): δ 189.6 (C=O), 164.2 (Car), 134.8 (Car), 128.7 (Car), 124.9(Car), 122.3(Car), 118.6 (Car), 65.2 (OCH2), 45.8 (NCH2); HRMS (ESI-TOF) m/z Calcd for C11H14NO5S [M+H]⁺ : 272.0587. Found 272.0578.

2,2'-(ethane-1,2-diylbis(methylazanediyl))bis(methylene)bis(4-(piperidin-1-ylsulfonyl)phenol) (5a): To a solution of 4a (1.7 g, 6.66 mmol) in CH2Cl2 (30 ml) was added ethylenediamine (198.3 mg, 3.3 mmol) at r.t. the reaction was allowed to proceed for another 12 h at r.t after which the yellow precipitates was collected by filtration and suspended in fresh CH2Cl2 (30 ml), NaBH4 (1.19 g, 31.45 mmol) was slowly added while maintaining the tempature at 0 ^oC. When adding was complete, the reaction was allowed to proceed for 12 h and warm to r.t. The reaction mixture was washed with saturated NH4Cl aqueous solution (5 ml) and extracted with CH2Cl2 (2 × 20 ml). The organic layer was dried over MgSO4, the solvent was evaporated in vacuo to give a crude solid which was used for the next step without further purification. To a stirred solution of the crude solid in CH3CN (50 ml) and CH3COOH (10 ml) was added formaldehyde 37 wt. % in H2O (2.46 ml, 32.3 mmol). The resulting suspension was stirred at r.t. for 1.5 h and cooled to 0 ^oC, NaBH4 (610 mg, 16 mmol) was slowly added. After complete addition, the reaction was allowed to warm to r.t. and monitered by TLC. After the reaction is complete the pH was adjusted to 7 by aqueous NaOH (1N), the reaction mixture was washed with H2O (15 ml) and extracted with CH2Cl2 (2 × 20 ml). The organic layer was dried over MgSO4, and the solvent was evaporated in vacuo to give 5a as a yellow solid (1.33 g, 23.46 mmol, 71 %). M.p. 205-207 ^oC; IR absorptions (cm^-1, ATR): 2967, 1582, 1482, 1472, 1329, 1145, 1007; ¹H NMR (CDCl3, 400 MHz): δ 7.64 (dd, J = 2.0, 8.4 Hz, 2H, Har), 7.48 (d, J = 2.0 Hz, 2H, Har), 6.92 (d, J = 8.4 Hz, 2H, Har), 3.77 (s, 4H, CarCH2), 3.19 (t, J = 4.0 Hz, 8H, NCH2), 2.70 (s, 4H, NCH2CH2N), 2.30 (s, 6H, NCH3), 1.76-1.73 (m, 8H, NCH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 162.0 (Car), 129.2

(Car), 128.6 (Car), 127.3 (Car), 121.7 (Car), 116.9 (Car), 61.3 (CarCH2), 53.8 (NCH2CH2N), 48.0 (NCH2), 41.6 (NCH3), 25.3 (NCH2CH2); ESI-MS m/z (%): 567 (95) [(M+H)⁺]; Anal. Calcd. for C26H38N4O6S2: C, 55.10; H, 6.76; N, 9.89. Found: C, 54.64; H, 6.67; N, 9.81.

2,2'((ethane1,2diylbis(methylazanediyl))bis(methylene))bis(4(pyrrolidin1ylsulfonyl) phen -ol) (5b): Following the same procedure as for 5a with 4b (3.1 g, 11.5 mm-ol), ethylenediamine (365 mg, 6.1 mmol) in MeOH (30 ml) for 2 h, then NaBH4 (1.32 g, 35 mmol) in 30 ml CH2Cl2 for 12 h.

Reductive amination was carried out using CH3COOH (17.1 ml), formaldehyde 37 wt. % in H2O (5 ml, 67 mmol), NaBH4 (761 mg, 20 mmol) in CH3CN (40 ml) give 5b as a yellow solid. (1.08 g, 1.82 mmol, 32 %). M.p. 190-191 ^oC; IR absorptions (cm^-1, ATR): 2838, 1589, 1332, 1322, 1159, 931, 725;

1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J = 6.8 Hz, 2H, Har), 7.46 (s, 2H, Har), 7.00 (d, J = 6.8 Hz, 2H, Har), 3.83 (s, 4H, CarCH2), 2.99 (t, J = 8.0 Hz, 8H, NCH2), 2.77 (s, 4H, NCH2CH2N), 2.36 (s, 6H, NCH3), 1.70-1.65 (m, 8H, NCH2CH2), 1.49-1.43 (m, 4H, NCH2CH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 162.0 (Car), 129.5 (Car), 128.7 (Car), 126.7 (Car), 121.7 (Car), 116.9 (Car), 61.4 (CarCH2), 53.9 (NCH2CH2N), 47.1 (NCH2), 41.7 (NCH3), 25.3 (NCH2CH2), 23.7 (NCH2CH2CH2); ESI-MS m/z (%):

595 (85) [(M+H)⁺]; Anal. Calcd. for C28H42N4O6S2: C, 56.54; H, 7.12; N, 9.42. Found: C, 56.55; H, 6.88; N, 9.24.

2,2'-((ethane-1,2-diylbis(methylazanediyl))bis(methylene))bis(4-(azepan-1-ylsulfonyl)phenol) (5c): Following the same procedure as for 5a with 4c (900 mg, 3.18 mmol), ethylenediamine (95 mg, 15.81 mmol), MeOH (15 ml) for 2 h then NaBH4 (350 mg, 9.25 mmol), CH2Cl2 (25 ml) for 2 h followed by CH3COOH (2.5 ml), formaldehyde 37 wt.% in H2O (1.5 ml, 19.69 mmol), NaBH4 (470 mg, 12.42 mmol), CH3CN (20 ml) for 12 h give 5c as a light yellow solid (370 mg, 0.59 mmol, 38 %).

M.p. 170-172 ^oC; IR absorptions (cm^-1, ATR): 2930, 1683, 1582, 1479, 1332, 1036, 922; ¹H NMR (d6-DMSO, 400 MHz): δ 7.57 (d, J = 2.0 Hz, 2H, Har), 7.50 (dd, J = 2.0, 8.8 Hz, 2H, Har), 6.88 (d, J

= 8.8 Hz, 2H, Har), 3.66 (s, 4H, CarCH2), 3.59 (t, J = 8.0 Hz, 8H, SO2NCH2), 2.66 (s, 4H, NCH2CH2N), 2.18 (s, 6H, NCH3), 1.57-1.53 (m, 8H, NCH2CH2), 1.47-1.43 (m, 8H, NCH2CH2CH2); ¹³C NMR (d6 -DMSO, 101 MHz): δ 160.6 (Car), 128.5 (Car), 128.4 (Car), 127.5 (Car), 124.1 (Car), 115.7 (Car), 56.7 (CarCH2), 53.4 (NCH2CH2N), 47.6 (NCH2), 41.2 (NCH3), 28.4 (NCH2CH2), 26.3 (NCH2CH2CH2);

HRMS (ESI-TOF) m/z Calcd for C30H47N4O6S2 [M+H]⁺: 623.2932. Found 623.2912.

 

2,2'-((ethane-1,2-diylbis(methylazanediyl))bis(methylene))bis(4-(morpholinosulfonyl) phenol) (5d): Following the same procedure as for 5a with 4d (2.22 g, 8.18 mmol), ethylenediamine (246 mg, 4.09 mmol), MeOH (25 ml) for 2 h then NaBH4 (100 mg, 2.64 mmol), CH2Cl2 (50 ml) for 2 h followed by CH3COOH (3.1 ml), formaldehyde 37 wt.% in H2O (1.07 ml, 14.05 mmol), NaBH4 (186 mg, 4.91 mmol), CH3CN (25 ml) for 12 h give 5d as a white solid (735.2 mg, 12.28 mmol, 28 %). M.p. 222-224 ^oC; IR absorptions (cm^-1, ATR): 2959, 1595,1488, 136, 1108, 949 735; ¹H NMR (d6-DMSO, 400 MHz): δ 7.55 (d, J = 2.0 Hz, 2H, Har), 7.48 (dd, J = 2.0, 8.8 Hz, 2H, Har), 6.94 (d, J = 8.8 Hz, 2H, Har), 3.70 (s, 4H, CarCH2), 3.59 (t, J = 4.0 Hz, 8H, OCH2), 2.79 (t, J = 4.0 Hz, 8H, NCH2), 2.66 (s, 4H, NCH2CH2N), 2.32 (s, 6H, NCH3); ¹³C NMR (d6-DMSO, 101 MHz): δ 161.5 (Car), 129.4 (Car), 128.6 (Car), 124.2 (Car), 123.5 (Car), 115.8 (Car), 65.2 (CarCH2), 56.6 (OCH2), 53.4 (NCH2CH2N), 45.9 (NCH2), 41.2 (NCH3); HRMS (ESI-TOF) m/z Calcd for C26H39N4O8S2 [M+H]⁺: 599.2204. Found 599.2203.

 

[Ti(4-(morpholinosulfonyl)N^Me)2(ⁱOPr)2] (6d): To an oven-dried, N2-purged flask containing 5d (400 mg, 0.66 mmol), in anhydrous THF (15 ml), Ti(OⁱPr)4 (208 mg, 0.73 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and the complete consumption of the free ligand was monitored by TLC. Solvent removal under vacuo gave the raw product as colorless solid (489.2 mg, 0.64 mmol, 96 %). Recrystallization of the raw product in anhydrous isopropanol and chloroform give pure 5d as a white solid. (226.1 mg, 0.30 mmol, 45 %). M.p. 210-212 ^oC; ¹H NMR (CDCl3, 400 MHz): δ 7.55 (dd, J = 8.7, 2.5 Hz, 2H, Har), 7.39 (d, J = 2.5 Hz, 2H, Har), 6.74 (d, J = 8.7 Hz, 2H, Har), 4.95 (sept, J = 5.9 Hz, 2H, OCH(CH3)2), 4.60 (d, J = 14.4 Hz, 2H, CarCH2), 3.74 (dt, J = 4.6 Hz, 8H, OCH2CH2N), 3.27 (d, J = 14.1 Hz, 2H, CarCH2), 2.98 (dt, J = 4.6 Hz, 8H, OCH2CH2N), 2.90 (d, J = 9.4 Hz, 2H, NCH2CH2N), 2.46 (s, 6H, NCH3), 1.94 (d, J = 9.4 Hz, 2H, NCH2CH2N), 1.25 (d, J = 6.5 Hz, 12H, OCH(CH3)2); ¹³C NMR (CDCl3, 101 MHz): δ 166.3 (Car), 130.2 (Car), 130.0 (Car), 124.4 (Car), 122.6 (Car), 118.3 (Car), 79.6 (OCH(CH3)2), 66.3 (OCH2CH2N), 51.9 (CarCH2), 47.5 (NCH3), 46.2 (OCH2CH2N), 26.0 (NCH2CH2N), 25.7 (OCH(CH3)), 25.5 (OCH(CH3)); UV/Vis (THF): λmax (ε) = 252 nm (8383 M^-1 cm^-1), 308 nm (10004 M^-1 cm^-1); Anal. Calcd. for C32H50N4O10S2Ti: C, 50.39; H, 6.61; N, 7.35. Found: C, 49.90; H, 6.55; N, 7.38.

[Ti(Ph4-(pyrrolidin-1-ylsulfonyl)N^Me)2(dipic)] (7a): Reactions were carried out with standard Schlenk techniques under a nitrogen atmosphere. To an oven-dried, N2-purged flask containing 5a (200 mg, 0.35 mmol) in anhydrous THF (10 ml), Ti(OⁱPr)4 (100 mg, 0.35 mmol) was added. The reaction mixture was stirred at r. t. for 14 h and monitored by TLC. Upon completion, the solvent was removed under vacuo, crude product was dissolved in 10 ml anhydrous THF and pyridine-2,6-dicarboxylic acid 8 (118 mg, 0.70 mmol) was added under N2 protection, the reaction was stirred for 24 h at r.t.

and was measured by TLC, upon finished, the solvent was evaporated, the residue was dissolved in 30 ml CH2Cl2 and washed by 1N NaOH then by brine, the organic phase was dried over MgSO4, the solvent was evaporated in vacuo to give a crude product which was purified by column chromatography on silica gel (DCM/MeOH = 10 : 1) to give 7a as a yellow solid (90.4 mg, 0.12 mmol, 33 %). M.p. 250-251 ^oC; IR absorptions (cm^-1, ATR): 2933, 1644, 1592, 1475, 1298, 1111, 945, 908, 783; ¹H NMR (CDCl3, 400 MHz): δ 8.36-8.32 (dd, J = 7.0, 8.0 Hz, 1H, HPyr), 8.24 (d, J = 7.0 Hz, 2H, HPyr), 7.58-7.54 (m, 4H, Har), 6.52 (d, J = 8.0 Hz, 2H, Har), 5.39 (d, J = 16.0 Hz, 2H, CarCH2), 3.37 (d, J = 16.0 Hz, 2H, CarCH2), 3.32 (d, J = 8.0 Hz, 2H, NCH2CH2N), 3.19-3.16 (m, 8H, NCH2), 2.82 (s, 6H, NCH3), 2.33 (d, J = 8.0 Hz, 2H, NCH2CH2N), 1.77-1.74 (m, 8H, NCH2CH2);

13C NMR (CDCl3, 101 MHz): δ 169.1 (C=O), 162.7 (Car), 149.5 (Car), 144.2 (Car), 129.7 (Car), 129.6 (Car), 129.3 (Car), 128.2 (Car), 126.3 (Car), 117.1 (Car), 63.9 (CarCH2), 54.3 (NCH2CH2N), 48.0 (NCH2), 47.7 (NCH3), 25.3 (NCH2CH2); UV/Vis (THF): λmax (ε) = 210 nm (33120 M^-1cm^-1), 240 nm (28330 M^-1cm^-1), 375 nm (10340 M^-1cm^-1); HRMS (ESI-TOF) m/z Calcd for C33H40N5O10S2Ti [M+H]⁺ : 778.1691. Found 778.1699.

[Ti(Ph4-(piperidin-1-ylsulfonyl)N^Me)2(dipic)] (7b): Following the same procedure as for 7a with 5b (200 mg, 0.34 mmol), Ti(OⁱPr)4 (105 mg, 0.37 mmol) in 10 ml anhydrous THF for 2 h (TLC control) then pyridine-2,6-dicarboxylic acid 8 (109 mg, 0.67 mmol) in 10 ml anhydrous THF give 7b as a yellow solid (107.6 mg, 0.133 mmol, 40 %). M.p. 210-212 ^oC; IR absorptions (cm^-1, ATR): 1682, 1478, 1337, 1264, 1144, 1050, 911, 796; ¹H NMR (CDCl3, 400 MHz): δ 8.34 (t, J = 8.0 Hz, 1H, Hpyr), 8.24 (d, J

= 8.0 Hz, 2H, Hpyr), 7.50-7.46 (m, 4H, Har), 6.51 (d, J = 8.0 Hz, 2H, Har), 5.40 (d, J = 16.0 Hz, 2H, CarCH2), 3.37 (d, J = 16.0 Hz, 2H, CarCH2), 3.32 (d, J = 8.0 Hz, 2H, NCH2CH2N), 2.96-2.88 (m, 8H, NCH2), 2.82 (s, 6H, NCH3), 2.33 (d, J = 8.0 Hz, 2H, NCH2CH2N), 1.62-1.59 (m, 8H, NCH2CH2), 1.41-1.38 (m, 4H, NCH2CH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 169.0 (C=O), 162.7 (Car), 149.5 (Car), 144.3 (Car), 129.6 (Car), 129.4 (Car), 128.9 (Car), 128.1 (Car), 126.3 (Car), 117.0 (Car), 63.9 (CarCH2), 54.2 (NCH2CH2N), 47.7 (NCH2), 47.0 (NCH3), 25.3 (NCH2CH2), 23.5 (NCH2CH2CH2);

UV/Vis (THF): λmax (ε) = 215 nm (29690 M^-1cm^-1), 240 nm (23870 M^-1cm^-1), 375 nm (8640 M^-1cm

-1); HRMS (ESI-TOF) m/z Calcd for C35H44N5O10S2Ti [M+H]⁺ : 806.2004. Found 806.1993.

[Ti(Ph4-(azepansulfonyl)N^Me)2(dipic)] (7c): Following the same procedure as for 7a with 5c (312 mg, 0.5 mmol), Ti(OⁱPr)4 (157 mg, 0.55 mmol) in 15 ml anhydrous THF for 2 h (TLC control) then pyridine-2,6-dicarboxylic acid 8 (162 mg, 1.0 mmol) in 15 ml anhydrous THF give 7c as a light yellow solid (165.3 mg, 0.20 mmol, 40 %). M.p. 225-227 ^oC; IR absorptions (cm^-1, ATR): 2930, 1689, 1478, 1337, 1308, 1146, 910, 795; ¹H NMR (CDCl3, 400 MHz): δ 8.35-8.32 (dd, J = 7.2, 8.4 Hz,1H, HPyr), 8.22 (d, J = 7.2 Hz, 2H, HPyr), 7.51-7.49 (m, 4H, Har), 6.48 (d, J = 8.8 Hz, 2H, Har), 5.37 (d, J = 14.6 Hz, 2H, CarCH2), 3.35 (d, J = 14.6 Hz, 2H, CarCH2), 3.30 (d, J = 8.0 Hz, 2H, NCH2CH2N), 3.19 (t, J = 4.0 Hz, 8H, NCH2), 2.80 (s, 6H, NCH3), 2.31 (d, J = 8.0 Hz, 2H, NCH2CH2N), 1.71-1.65 (m, 8H, NCH2CH2) 1.57-1.55 (m, 8H, NCH2CH2CH2); ¹³C NMR (CDCl3, 101 MHz): δ 169.0 (C=O), 162.4 (Car), 149.5 (Car), 144.2 (Car), 132.2 (Car), 129.0 (Car), 128.6 (Car), 128.1 (Car), 126.3 (Car), 117.0 (Car), 63.9 (CarCH2), 54.3 (NCH2CH2N), 48.2 (NCH2), 47.7 (NCH3), 29.2 (NCH2CH2), 27.0 (NCH2CH2CH2); UV/Vis (THF): λmax (ε) = 210 nm (18360 M^-1cm^-1), 242 nm (10180 M^-1cm^-1), 375 nm (4054 M^-1cm^-1); HRMS (ESI-TOF) m/z Calcd for C37H48N5O10S2Ti [M+H]⁺ : 834.2317. Found 834.2279.

[Ti(Ph4-(morpholinosulfonyl)N^Me)2(dipic)] (7d): Following the same procedure as for 7a with 5d (300 mg, 0.5 mmol), Ti(OⁱPr)4 (157 mg, 0.55 mmol) in 15 ml anhydrous THF for 2 h (TLC control) then pyridine-2,6-dicarboxylic acid 8 (162 mg, 1.0 mmol) in 15 ml anhydrous THF give 7d as a yellow solid (179 mg, 0.22 mmol, 45 %). M.p. 267-268 ^oC; IR absorptions (cm^-1, ATR): 2929, 1591, 1480, 1299, 1110, 944, 909, 793; ¹H NMR (d6-acetone, 400 MHz): δ 8.63 (t, J = 8.0 Hz, 1H, HPyr), 8.27 (d, J = 8.0 Hz, 2H, HPyr), 7.59-7.49 (m, 4H, Har), 6.60 (d, J = 8.0 Hz, 2H, Har), 5.32 (d, J = 16.0 Hz, 2H, CarCH2), 3.70 (d, J = 16.0 Hz, 2H, CarCH2), 3.64 (t, J = 4.0 Hz, 8H, OCH2), 3.41 (d, J = 8.0 Hz, 2H, NCH2CH2N), 2.89 (t, J = 4.0 Hz, 8H, NCH2), 2.86 (s, 6H, NCH3), 2.60 (d, J = 8.0 Hz, 2H, NCH2CH2N); ¹³C NMR (d6-acetone, 101 MHz): δ 169.1 (C=O), 164.2 (Car), 150.1 (Car), 146.4 (Car), 131.0 (Car), 130.4 (Car), 129.7 (Car), 128.3 (Car), 127.1 (Car), 117.8 (Car), 66.7 (OCH2), 63.9 (CarCH2), 54.8 (NCH2CH2N), 47.9 (NCH3), 47.1 (OCH2CH2N); UV/Vis (THF): λmax (ε) = 210 nm (27190 M

-1cm^-1), 245 nm (15900 M^-1cm^-1), 360 nm (5930 M^-1cm^-1); HRMS (ESI-TOF) m/z Calcd for C33H40N5O12S2Ti [M+H]⁺ : 810.1589. Found 810.1608.

 

[Ti(PhN^Me)2(dipic)] (7e): Following the same procedure as for 7a reacting 5e^[164] (500 mg, 1.7 mmol), Ti(OⁱPr)4 (567.9 mg, 2.0 mmol) in anhydrous THF (15 ml) for 2 h (TLC control) then adding pyridine-2,6-dicarboxylic acid 8 (324 mg, 2.0 mmol) in anhydrous THF (20 ml) gives after purification by column chromatography 7e as a red solid (368 mg, 0.7 mmol, 44 %). M.p. 221 ^oC (decomp.); IR absorptions (cm^-1, ATR): 1678, 1480, 1340, 1258, 1242, 1177, 1069, 893, 739; ¹H NMR (CDCl3, 400 MHz): δ 8.27 (dd, J = 6.8, 8.8 Hz, 1H, HPyr), 8.18 (d, J = 7.2 Hz, 2H, HPyr), 7.08-7.04 (m, 4H, Har), 7.0 (d, J = 7.2 Hz, 2H, Har), 6.81 (td, J = 7.2, 0.8 Hz, 2H, Har), 6.4 (d, J = 8.8 Hz, 2H, Har), 5.37 (d, J

= 14.4 Hz, 2H, CHar), 3.37 (d, J = 9.2 Hz, 2H, NCH2CH2N), 3.23 (d, J = 14.4 Hz, 2H, CarCH2), 2.80 (s, 6H, NCH3), 2.19 (d, J = 9.2 Hz, 2H, NCH2CH2N); ¹³C NMR (CDCl3, 101 MHz): δ 169.0 (C=O), 159.6 (Car), 149.9 (Car), 143.5 (Car), 129.7 (Car), 129.0 (Car), 128.1 (Car), 128.1 (Car), 125.9 (Car), 121.7 (Car), 116.4 (Car), 64.2 (CarCH2), 54.0 (NCH2CH2N), 47.7 (NCH3); UV/Vis (THF): λmax (ε) = 215 nm (23240 M^-1cm^-1), 380 nm (6350 M^-1cm^-1); HRMS (ESI-TOF) m/z Calcd for C25H25N3O6Ti [M+H]⁺: 512.1296, found: 512.1316.

 

2-azidoethyl 4-methylbenzenesulfonate (15a): Following the literature reported method,^[165]

azidoethanol 14a (7.37 g, 84.5 mmol in 154 ml THF and 37 ml DMF), tosyl chloride (18.57 g, 97.7 mmol) and triethylamine (25.7 g, 0.25 mol) were mixed in a 500 ml round bottom flask. The reaction mixture was stirred for overnight with the progress of the reaction being monitored by TLC. After completion, THF was removed under reduced pressure; the crude product was dissolved in 150 ml EtOAc. The organic layer was then washed with water, 1N HCl (3 × 20 ml), 10% NaOH (3 × 20 ml), and saturated brine solution. The organic layer was then dried over MgSO4, filtered and concentrated to give 15a as red oil (189.4 mg, 78.5 mmol, 92 %).¹H NMR (CDCl3, 400 MHz): δ 7.80 (d, J = 8.0

Hz, 2H, Har), 7.36 (d, J = 8.0 Hz, 2H, Har), 4.15 (t, J = 4.0 Hz, 2H, OCH2), 3.47 (t, J = 4.0 Hz, 2H, N3CH2), 2.44 (s, 3H, CH3); ¹³C NMR (CDCl3, 101 MHz): δ 145.3 (Car), 132.6 (Car), 130.1 (Car), 128.0 (Car), 68.2 (OCH2), 49.7 (N3CH2), 21.7 (CH3). 

 

2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate^[166] (15b): Following the same procedure as for 15a with 2-(2-azidoethoxy)ethan-1-ol 14b (2 g, 15.2 mmol), tosyl chloride (4.36 g, 22.8 mmol) and triethylamine (20.6 g, 0.2 mol) give 15b as a yellow oil (3.9 g, 13.6 mmol, 90 %). ¹H NMR (CDCl3, 400 MHz): δ 7.79 (AA’ of AA’BB’, J = 8.0 Hz, 2H, Har), 7.34 (BB’ of AA’BB’, J = 8.0 Hz, 2H, Har), 4.16 (t, J = 4.0 Hz, 2H, OCH2), 3.68 (t, J = 4.0 Hz, 2H), 3.68 (t, J = 4.0 Hz, 2H, OCH2), 3.59 (t, J = 4.0 Hz, 2H, OCH2), 3.30 (t, J = 4.0 Hz, 2H, CH2N3), 2.44 (s, 3H, CH3); ¹³C NMR (CDCl3, 101 MHz):

δ 145.0 (SO2Car), 133.0 (Car), 130.0 (Car), 128.1 (Car), 70.3 (OCH2), 69.2 (OCH2), 68.8 (OCH2), 50.7 (CH2N3), 21.8 (CH3);

 

2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate^[167] (15c): Following the same procedure as for 15a with 2-(2-(2-azidoethoxy)ethoxy)ethan-1-ol 14c (29 g, 11.3 mmol), tosyl chloride (6.76 g, 6.8 mmol) and triethylamine (20.6 g, 0.2 mol) give 15c as a yellow oil (3.07 g, 9.26 mmol, 83 %). ¹H NMR (CDCl3, 400 MHz): δ 7.74 (AA’ of AA’BB’ J = 8.0 Hz, 2H, Har), 7.30 (BB’

of AA’BB’ J = 8.0 Hz, 2H, Har), 4.11 (t, J = 4.0 Hz, 2H, OCH2), 3.65-3.54 (m, 8H, Hal), 3.31 (t, J = 4.0 Hz, 2H, CH2N3), 2.40 (s, 3H, CH3); ¹³C NMR (CDCl3, 101 MHz): δ 144.8 (Car), 132.9 (Car), 129.8 (Car), 127.9 (Car), 70.7 (OCH2), 70.5 (OCH2), 70.0 (OCH2), 69.3 (OCH2), 68.7 (OCH2), 50.6 (N3CH2), 21.6 (CH3).

 

2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate^[168] (15d): Following the same procedure as for 15a with 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy) ethan-1-ol 14d (3 g, 13.5 mmol), tosyl chloride (3.83 g, 2.03 mmol) and triethylamine (20.6 g, 0.2 mol) give 15d as a white solid (4.31 g, 11.63 mmol, 88 %). ¹H NMR (CDCl3, 400 MHz): δ 7.75 (AA’ of AA’BB’ J = 8.0 Hz,

2H, Har), 7.31 (BB’ of AA’BB’ J = 8.0 Hz, 2H, Har), 4.12 (t, J = 4.0 Hz, 2H, OCH2), 3.66-3.55 (m, 12H, Hal), 3.34 (t, J = 4.0 Hz, 2H, CH2N3), 2.41 (s, 3H, CH3); ¹³C NMR (CDCl3, 101 MHz): δ 144.8 (Car), 132.9 (Car), 129.8 (Car), 127.9 (Car), 70.7 (OCH2), 70.6 (OCH2), 70.5 (OCH2), 70.0 (OCH2), 69.3 (OCH2), 68.6 (OCH2), 50.6 (N3CH2), 21.6 (CH3).

Dimethyl (2-azidoethoxy) pyridine-2,6-dicarboxylate (16a): To a solution of dimethyl 4-hydroxypyridine-2,6-dicarboxylate 11 (520 mg, 2.48 mmol) and 2-azidoethyl 4-methyl benzenesulfonate 15a (600 mg, 2.49 mmol) in 20 ml DMF was added K2CO3 (1.71g, 12.3 mmol).

The reaction mixture was heated to 80 ^oC for overnight and was measured by TLC, upon finished, the reaction was washed by H2O (3 × 20 ml) and extracted by 50 ml EtOAc, the organic layer was separated and dried over MgSO4, the solvent was removed under reduced pressure to give compound 16a as a white solid. (500 mg, 1.7 mmol, 74%). M.p. 111 °C; ¹H NMR (CDCl3, 400 MHz): δ 7.83 (s, 2H, Hpyr), 4.31 (t, J = 4.0 Hz, 2H, OCH2), 4.01 (s, 6H, OCH3) 3.69 (t, J = 4.0 Hz, 2H, OCH2); ¹³C NMR (CDCl3, 101 MHz): 165.9 (C=O), 164.5 (Cpyr), 149.4 (Cpyr), 114.1 (Cpyr), 67.9 (OCH2), 52.7 (OCH2), 49.2 (N3CH2). HRMS (ESI-TOF) m/z Calcd for C11H13N4O5 [M+H]⁺: 281.0880. Found 281.0884; Anal. Calcd. for C11H12N4O5: C, 47.15; H, 4.32; N, 19.99; O, 28.55. Found C, 47.21; H, 4.39; N 19.76.

Dimethyl 4-(2-(2-azidoethoxy)ethoxy)pyridine-2,6-dicarboxylate (16b): Following the same procedure as for 16a with 4-hydroxypyridine-2,6-dicarboxylate 11 (2.69 g, 14.02 mmol), 2-(2-azidoethoxy)ethyl 4-methylbenzenesulfonate 15b (4 g, 14.02 mmol) and K2CO3 (8.84 g, 63.9 mmol) in 50 ml DMF for overnight to give 16b as a white solid (3.32 g, 10.2 mmol, 73 %). This compound was directly put into the next step without further purification. M.p. 62 °C-64 °C; ¹H NMR (d6-DMSO, 400 MHz): δ 7.75 (s, 2H, HPyr), 4.40-4.37 (m, 2H, OCH2), 3.90 (s, 6H, CH3), 3.84-3.82 (m, 2H,

OCH2), 3.68 (t, J = 8.0 Hz, 2H, OCH2), 3.40 (t, J = 8.0 Hz, 2H, CH2N3); ¹³C NMR (d6-DMSO, 101 MHz): δ 166.4 (C=O), 164.6 (Car), 149.3 (Car), 114.2 (Car), 69.4 (OCH2), 69.3 (OCH2), 68.3 (OCH2), 52.7 (OCH3), 49.9 (N3CH2); HRMS (ESI-TOF) m/z Calcd for C13H17N4O6 [M+H] ⁺ : 325.1143. Found 325.1151.

Dimethyl4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)pyridine-2,6-dicarboxylate^[169] (16c): Following the same procedure as for 16a with 4-hydroxypyridine-2,6-dicarboxylate 11 (1.5 g, 8.2 mmol), 15c (4.04 g, 12.2 mmol) and K2CO3 (6.79 g, 49.2 mmol) in 50 ml DMF for overnight to give 16c as a white solid (2.41 g, 6.5 mmol, 80 %). This compound was directly put into the next step without further purification. ¹H NMR (CDCl3, 400 MHz): δ 7.77 (s, 2H, Hpyr), 4.25(t, J = 4.6 Hz, 2H, OCH2), 3.93 (s, 6H, CH3), 3.85 (t, J = 4.8 Hz, 2H, OCH2), 3.67-3.65 (m, 2H, OCH2), 3.63-3.58 (m, 4H, OCH2), 3.31 (t, J = 5.0 Hz, 2H, CH2N3).

 

Dimethyl4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyridine-2,6-dicarboxylate(16d):

Following the same procedure as for 16a with 4-hydroxypyridine-2,6-dicarboxylate 11 (1.0 g, 5.4 mmol), 15d (4.07 g, 8.1 mmol) and K2CO3 (4.47 g, 32.4 mmol) in 50 ml DMF for overnight to give 16d as a white solid (1.78 g, 4.42 mmol, 82 %). This compound was put into the next step without further purification. ¹H NMR (CDCl3, 400 MHz): δ 7.75 (s, 2H, HPyr), 4.37(t, J = 4.7 Hz, 2H, OCH2), 3.91 (s, 6H, CH3), 3.80 (t, J = 4.7 Hz, 2H, OCH2), 3.66-3.51 (m, 12H, OCH2) 3.31 (t, J = 5.0 Hz, 2H, CH2N3).

4-(2-azidoethoxy)pyridine-2,6-dicarboxylic acid (17a): KOH (440 mg, 7.9 mmol) dissolved in 30 ml EtOH was heated to 80 ^oC, 16a (470 mg, 1.7 mmol) was added to this solution; the reaction was stirred at 80 ^oC for 3 h and monitored by TLC. Upon completion, the solvent was removed under reduced pressure. The pH was adjusted to 3 by adding 1N HCl, and extracted by EtOAc (2 × 30 ml), the organic phase was separated and dried over MgSO4, and the solvent was removed under reduced pressure to give 17a as a white solid (350 mg, 88.26 mmol, 83 %). M.p. 120 °C-121 °C; ¹H NMR (d6-DMSO, 400 MHz): δ 7.73 (s, 2H, Hpyr), 4.44 (t, J = 4.0 Hz, 2H, OCH2), 3.72 (t, J = 4.0 Hz, 2H, N3CH2); ¹³C NMR (d6-DMSO, 101 MHz): δ 166.1 (C-O), 165.2 (C=O), 149.9 (CNC), 113.6 (CH), 67.9 (CH2), 49.2 (N3CH2); HRMS (ESI-TOF) m/z Calcd for C9H9N4O5 [M+H] ⁺: 253.0567. Found 253.0568.

4-(2-(2-azidoethoxy)ethoxy)pyridine-2,6-dicarboxylic acid (17b): Following the same procedure as for 17a with 16b (1.01 g, 3.1 mmol), K2CO3 (2.15 g, 15.5 mmol) in 50 ml EtOH to give 17b as a white solid. (0.87 g, 2.93 mmol, 95 %). M.p. Decomposition at 111 ^oC; ¹H NMR (d6-DMSO, 400 MHz): δ 7.72 (s, 2H, Hpyr), 4.38 (t, J = 4.0 Hz, 2H, OCH2), 3.83 (t, J = 4.0 Hz, 2H, OCH2), 3.68 (t, J

= 4.0 Hz, 2H, OCH2), 3.40 (t, J = 4.0 Hz, 2H, CH2N3); ¹³C NMR (d6-DMSO, 400 MHz): δ 166.7 (C=O), 166.5 (Cpyr), 149.6 (Cpyr), 113.6 (Cpyr), 69.4 (OCH2), 68.3 (OCH2), 68.3 (OCH2), 49.9 (CH2N3);

HRMS (ESI-TOF) m/z Calcd for C11H11N4O6 [M-H]^- : 295.0684. Found 295.0693.

 

4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)pyridine-2,6-dicarboxylic acid^[169] (17c): Following the same procedure as for 17a with 16c (1.14 g, 3.1 mmol), K2CO3 (2.15 g, 15.5 mmol) in 50 ml EtOH to give 17c as a white solid. (0.87 g, 2.54 mmol, 82 %). ¹H NMR (d6-DMSO, 400 MHz): δ 7.72 (s, 2H, Hpyr), 4.36 (t, J = 4.0 Hz, 2H, OCH2), 3.79 (t, J = 4.0 Hz, 2H, OCH2), 3.62-3.54 (m, 6H, OCH2), 3.36 (t, J = 4.0 Hz, N3CH2); ¹³C NMR (d6-DMSO, 400 MHz): δ 166.8 (C=O), 165.2 (Car), 149.7 (Car), 113.5 (Car), 70.0 (OCH2), 69.7 (OCH2), 69.3 (OCH2), 68.5 (OCH2), 68.3 (OCH2), 50.0 (N3CH2);

HRMS (ESI-TOF) m/z Calcd for C13H15N4O7 [M-H]^-: 339.0935. Found 339.0954.

 

4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyridine-2,6-dicarboxylicacid(17d): Following the same procedure as for 17a with 16d (1.27 g, 3.1 mmol), K2CO3 (2.15 g, 15.5 mmol) in 50 ml EtOH to give 17d as a white solid. (0.93 g, 2.4 mmol, 78 %). ¹H NMR (d6-DMSO, 400 MHz): δ 7.71 (s, 2H, Hpyr), 4.35 (t, J = 4.5 Hz, 2H, OCH2), 3.78 (t, J = 4.5 Hz, 2H, OCH2), 3.62-3.45 (m, 12H, OCH2, CH2N3); HRMS (ESI-TOF) m/z Calcd for C15H19N4O8 [M-H]^-: 383.1208. Found 383.1199.

 

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-azidoethoxy))] (19a): Reactions was carried out with standard Schlenk techniques under a nitrogen atmosphere. To an oven-dried, N2-purged flask containing 6f (400 mg, 0.15 mmol) in anhydrous THF (10 ml), 17a (635 mg, 0.12 mmol) was added. The reaction turns red immediately. The reaction mixture was stirred at r.t. for 12 h and monitored by TLC, upon completion, the solvent was evaporated, the crude product was dissolved in CH2Cl2 and purified by flash

chromatography (PE/EA = 3 then CH2Cl2/MeOH = 10 : 1). The solvent was removed under reduced pressure to give 19a as a red solid (729 mg, 1.1 mmol, 92 %). M.p.: Decomposition > 250°C; IR absorptions (cm^-1, ATR): 2913, 2096, 1673, 1619, 1472, 1369, 1243, 1054, 947, 850, 746; ¹H NMR (CDCl3, 400 MHz): δ 7.62 (s, 2H, Hpyr), 6.76 (s, 2H, Har), 6.65 (s, 2H, Har), 5.26 (d, J = 16.0 Hz, 2H, CarCH2), 4.36 (t, J = 4.0 Hz, 2H, OCH2), 3.70 (t, J = 4.0 Hz, 2H, N3CH2), 3.36 (d, J = 8.0 Hz, 2H NCH2), 3.14 (d, J = 16.0 Hz, 2H, CarCH2), 2.75 (s, 6H, NCH3), 2.19 (s, 6H, NCH3), 2.11 (d, J = 8.0 Hz, 2H NCH2), 1.93 (s, ArCH3); ¹³C NMR (CDCl3, 101 MHz): δ 169.0 (C=O), 168.9 (Car), 156.1 (Car), 152.1 (Car), 130.7 (Car), 130.5 (Car), 127.8 (Car), 127.4 (Car), 125.0 (Car), 111.2 (Car), 68.8 (OCH2), 64.0 (CarCH2), 53.9 (NCH2), 49.7 (N3CH2), 47.1 (NCH3), 20.7 (ArCH3), 16.0 (ArCH3);

HRMS (ESI-TOF) m/z Calcd for C31H37N6O7Ti [M+H]⁺ : 653.2198. Found 653.2192.

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(2-azidoethoxy)ethoxy))] (19b): Following the same procedure as for 19a with 6f (1.05 g, 2.03 mmol), 17b (900 mg, 3.03 mmol) in 45 ml anhydrous THF for 12 h to give 19b as a red solid (594 mg, 0.85 mmol, 44 %). M.p.: Decomposition > 240°C; IR absorptions (cm^-1, ATR): 2910, 2106, 1678, 1619, 1473, 1352, 1245, 1123, 1057, 947, 850, 746; ¹H NMR (CDCl3, 400 MHz): δ 7.61 (s, 2H, HPyr), 6.76 (s, 2H, Har), 6.65 (s, 2H, Har), 5.27 (d, J = 12.0 Hz, 2H, CarCH2), 4.39-4.36 (m, 2H, OCH2), 3.92 (t, J = 4.0 Hz, 2H , OCH2), 3.74 (t, J = 4.0 Hz, OCH2), 3.40 (t, J = 4.0 Hz, CH2N3), 3.76 (d, J = 8.0 Hz, NCH2), 3.13 (d, J = 12.0 Hz, 2H, CarCH2), 2.75 (s, 6H, NCH3), 2.19 (s, 6H, ArCH3), 2.11 (d, J = 8.0 Hz, NCH2), 1.93 (s, 6H, ArCH3); ¹³C NMR (CDCl3, 101 MHz): δ 170.5 (C=O), 169.0 (Car), 156.1 (Car), 152.0 (Car), 130.7 (Car), 130.5 (Car), 127.8 (Car), 127.4 (Car), 125.0 (Car), 111.3 (Car), 70.6 (OCH2), 69.4 (OCH2), 69.0 (OCH2), 64.0 (CarCH2), 53.9 (NCH2), 50.8 (N3CH2), 47.1 (NCH3), 20.8 (ArCH3), 16.0 (ArCH3); HRMS (ESI-TOF) m/z Calcd for C33H41N6O8Ti [M+H]⁺ 697.2460.

Found 687.2436.

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy))] (19c): Following the same procedure as for 19a with 6f (407 mg, 0.78 mmol), 17c (400 mg, 1.17 mmol) in 20 ml anhydrous THF for 16 h to give 19c as a red solid (394 mg, 0.53 mmol, 68 %). M.p.: 105-107 ^oC; IR absorptions (cm^-1, ATR): 2981, 1673, 1381, 1249, 1151, 951, 848; ¹H NMR (CDCl3, 400 MHz): δ 7.61 (s, 2H, Hpyr), 6.76 (s, 2H, Har), 6.64 (s, 2H, Har), 5.26 (d, J = 16.0 Hz, 2H, CarCH2), 4.38 (d, J = 4.0 Hz, 2H, OCH2), 3.92 (t, J = 4.0 Hz, 2H, OCH2), 3.73-3.71 (m, 2H, OCH2), 3.68-3.67 (m, 2H, OCH2), 3.65 (d, J = 8.0 Hz, 2H, NCH2), 3.39-3.35 (m, 4H, N3CH2CH2), 3.13 (d, J = 16.0 Hz, 2H, CarCH2), 2.74 (s, 6H, NCH3), 2.19 (s, 6H, CarCH3), 2.11 (d, J = 8.0 Hz, 2H, NCH2), 1.93 (s, 6H, CarCH3); ¹³C NMR (CDCl3, 101 MHz): δ 170.7 (C=O), 169.1 (Car), 156.1 (Car), 151.9 (Car), 130.6 (Car), 130.4 (Car), 127.8 (Car), 127.4 (Car), 125.0 (Car), 111.4 (Car), 71.2 (OCH2), 70.8 (OCH2), 70.3 (OCH2), 69.6 (OCH2), 69.2 (OCH2), 64.0 (CarCH2), 53.8 (NCH2), 50.8 (N3CH2), 47.1 (NCH3), 20.8 (CarCH3), 16.0 (CarCH3); HRMS (ESI-TOF) m/z Calcd for C35H45N6O9Ti [M+H] ⁺ 741.2722. Found: 741.2705.

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy))] (19d): Following the same procedure as for 19a with 6f (902 mg, 1.70 mmol), 17d (1.0 g, 2.60 mmol) in 50 ml anhydrous THF for 16 h to give 19d as a red solid (352 mg, 0.45 mmol, 26 %). IR absorptions (cm^-1, ATR): 2860, 2100, 1676, 1618, 1473, 1349, 1244, 1118, 1055, 850; ¹H NMR (d6-acetone, 400 MHz): δ 7.58 (s, 2H, Hpyr), 6.77 (d, J = 8.0 Hz, 2H, Har), 5.17 (d, J = 12.0 Hz, 2H, CarCH2), 4.59 (t, J = 4.0 Hz, 2H, OCH2), 3.95 (t, J

= 4.0 Hz, 2H, OCH2), 3.69-3.58 (m, 8H, OCH2 and NCH2), 3.31-3.28 (m, 6H, CarCH2 and OCH2), 2.74 (s, 6H, NCH3), 2.31 (d, J = 8.0 Hz, 2H, N3CH2), 2.18-2.16 (m, 8H, CarCH3 and NCH2), 1.90 (s, 6H, CarCH3); ¹³C NMR (d6-acetone, 101 MHz): δ 171.2 (C=O), 167.9 (Car), 156.1 (Car), 151.8 (Car), 130.2 (Car), 129.8 (Car), 127.8 (Car), 127.4 (Car), 124.2 (Car), 110.8 (Car), 70.6 (OCH2), 70.4 (OCH2), 70.3 (OCH2), 69.9 (OCH2), 69.8 (OCH2), 69.0 (OCH2), 63.2 (CarCH2), 53.4 (NCH2), 50.5 (N3CH2), 46.1 (NCH3), 19.8 (CarCH3), 15.1 (CarCH3); HRMS (ESI-TOF) m/z Calcd for C37H49N6O10Ti [M+H]⁺ 785.2984. Found 785.2971.

(E)-3-bromo-2-oxopropanal oxime (22): Following the literature reported method,^[170] in a 100 ml bottle, three necked flask equipped with a dropping funnel, thermometer and magnetic stirring bar was added a solution of fresh distilled diketene 20 (4.2 g, 50 mmol) in 50 ml CH2Cl2. Bromine (8.0 g, 50 mmol) dissolved in 20 ml CH2Cl2 was added slowly under stirring while maintain the temperature between -2 ^oC to 2 ^oC. Bromine was added especially slowly near the equivalent point.

After complete addition, the solvent was removed under vacuo; the crude γ -bromoacetoacetyl bromide 21 was dissolved 50 ml absolute ether. A solution of NaNO2 (3.45, 50 mol) in 38 ml H2O was placed in a three necked flask and cooled to 0 ^oC, under efficient mechanical stirring, the ether solution of γ -bromoacetoacetyl bromide 21 was added drop wise while maintain the temperature below 5 ^oC, after complete addition, the two phase mixture was stirred for another 15 min at r.t. the two layer was then separated, and the aqueous layer was extracted with three 50-ml portions of ether.

The combined ether layers were dried over Na2SO4, and concentrated on a rotary evaporator. The crude product was recrystallized in CCl4 to give 21 as a waxy solid. (5.79 g, 34.9 mol, 70 %). M.p.:

78-79 ^oC; ¹H NMR (CDCl3, 400 MHz): δ 7.63 (s, 1H, N=CH), 4.32 (s, 2H, CH2Br); ¹³C NMR (CDCl3, 101 MHz): δ 189.7 (C=O), 147.5 (N=CH), 30.3 (CH2Br).

6-(bromomethyl)pteridine-2,4-diamine^[106] (24): To a boiling solution of pyrimidine-2,4,5,6-tetraamine hydro-bromide 22 (3.0 g, 13.6 mol) in 60 ml methanol, (E)-3-bromo-2-oxopropanal oxime 23 (2.49 g, 15 mol) dissolved in 30 ml methanol was added. The reaction was stirred for another 2 h and cool to r.t. ammonium solution was added to adjust the pH to 8, red precipitate was collected by filtration and dried under vacuo to give 24 as a red solid (1.69 g, 6.7 mol, 50 %). This compound dissolved pooly in organic solvent, ¹H NMR in [D6]-DMSO should be measured fast to prevent from degradation. ¹H NMR (CDCl3, 400 MHz): δ 8.84 (s, 1H, Har), 7.70 (s, 2H, NH2), 6.82 (s, 2H, NH2), 4.8 (s, 4H, CH2Br); EI-MS m/z (%): 253.9 (100) [M+H]⁺.

 

2-amino-6-(bromomethyl)-4a,8a-dihydropteridin-4(3H)-one (39): Following the literature reported method,^[111] a solution of 6-(bromomethyl)pteridine-2,4-diamine 24 (500 mg, 1.96 mol) in HBr (5.6 ml, 33 % in acetic acid) was heated to 95 ^oC for 30 min, when cooling down, orange precipitate formed and was collected by filtration to give compound 39 as an orange solid (256 mg, 1 mol, 52 %). ¹H NMR (CDCl3, 400 MHz): δ 9.03 (s, 1H, Har), 4.87 (s, 2H, CH2Br); ¹³C NMR (CDCl3, 101 MHz): δ 162.8 (C=O), 155.9 (C=N), 153.7 (C=N), 148.5 (N-C=N), 145.0 (NCHN), 121.3 (NCH), 62.1 (CH2Br). EI-MS m/z (%): 255 (100) [M-H]⁺.

 

Prop-2-yn-1-yl 4-aminobenzoate^[171] (25): To a solution of DCC (9.0 g, 43.8 mmol) and DMAP (5.3 g, 43.8 mmol) in 30 ml CH2Cl2, was added 4-aminobenzoic acid (5.0 g, 36.5 mmol), the mixture was stirred for 30 min at r.t. Propargyl alcohol 9 (1.59 ml, 43.8 mmol) was added, the reaction mixture was stirred for 24 h at r.t. After filtrate the precipitate, the crude product was purified by flash chromatography (PE/EA = 3:1) to give 25 as a white solid. (4.1 g, 23.4 mmol, 65 %). ¹H NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 12.0 Hz, 2H, Har), 6.63 (d, J = 12.0 Hz, 2H, Har), 4.87 (d, J = 4.0 Hz, 2H,

OCH2), 2.48 (t, J = 4.0 Hz, 1H, Halkyne); ¹³C NMR (CDCl3, 101 MHz): δ 165.9 (C=O), 151.3 (Car), 132.1(Car), 118.9 (Car), 113.9 (Car), 78.4 (Calkyne), 74.7 (Calkyne), 52.0 (OCH2).

4-ethynylaniline^[172] (36): To a solution of 4-iodoaniline 33 (900 mg, 4.1 mmol), TMSA 34 (0.6 ml, 4.2 mmol) in 15 ml Et3N, was added Pd(PPh3)2Cl2 (12 mg, 0.017 mmol), CuI (6 mg, 0.03 mmol), the reaction mixture was stirred under N2 at r.t. for 20 h. the solvent was removed in vacuo. The residue was purified by flash chromatography (PE/EA = 10 : 1) to give the crude product which was used in the next step without further purification. The crude product was dissolved in 36 ml CH2Cl2 and 75 ml MeOH, K2CO3 (1.26 g, 9.13 mmol), the reaction was stirred at r.t. for 15 h, 50 ml H2O was added and extracted with EtOAc (3 ×20 ml), the organic phase was combined and dried over MgSO4. the solvent was removed under vacuo, the residue was purified by flash chromatography (PE/EA = 5:1) to give 36 as a yellow solid. (416 mg, 3.56 mmol, 87 %). ¹H NMR (CDCl3, 400 MHz): δ 7.29 (d, J = 8.0 Hz, 2H, Har), 6.59 (d, J = 8.0 Hz, 2H, Har), 2.95 (s, H, Halkyne).

4-ethynyl-N-methylaniline^[173] (42): 4-iodo-N-methylaniline 40 was prepared according to the literature reported method.^[174] To a solution of 4-iodo-N-methylaniline 40 (500 mg, 2.1 mmol) and TMSA 34 (0.31 ml, 2.1 mmol) in 8 ml Et3N, was added Pd(PPh3)2Cl2 (6.1 mg, 0.009 mmol), CuI (3 mg, 0.016 mmol), the reaction was stirred under N2 for 15 h, then the solvent was evaporated under vacuo, extracted with CH2Cl2 (3 × 20 ml), the organic phase was combined and dried with MgSO4. After remove the solvent, the crude product was used in the next step without further purification. To a solution of the crude product in 27 ml CH2Cl2 and 50 ml MeOH, K2CO3 (967 mg, 7 mmol) was added, the reaction was heated to 50 ^oC and stirred for 24 h, the solvent was removed, the crude product was purified by flash chromatography (PE/EA = 3) to give 42 as a yellow solid (244 mg, 1.86 mmol, 87 %). ¹H NMR (CDCl3, 400 MHz): δ 7.33 (d, J = 8.0 Hz, 2H, Har), 6.51 (d, J = 8.0 Hz, 2H, Har), 2.97 (s, H, Halkyne), 2.83 (s, 6H, NCH3).

Prop-2-yn-1-yl 4-(((2,4-diaminopteridin-yl)methyl)amino)benzoate (27): To a solution of 6-(bromomethyl)pteridine-2,4-diamine 24 (400 mg, 1.57 mmol) in 20 ml DMA, was added prop-2-yn-1-yl 4-aminobenzoate 25 (414 mg, 2.36 mmol), the reaction was stirred at r.t. for 24 h, 50 ml H2O was added to the reaction mixture and cooled to 0 ^oC. Brown precipitates was collected by filtration and dried under vacuo to give 27 as a brown solid (253 mg, 0.72 mmol, 49 %). EI-MS m/z (%): 350 (100) [M+H]⁺.

(2,4-diaminopteridin-6-yl)methyl 4-ethynylbenzoate (28): To a solution of 6-(bromomethyl) pteridine-2,4-diamine 24 (232 mg, 0.9 mmol) in 10 ml DMF, was added K2CO3 (567 mg, 4.1 mmol) and 4-ethynylbenzoic acid 26 (200 mg, 1.37 mmol), the reaction was stirred at r.t. for 24 h, and 50 ml H2O was added to the reaction mixture and cooled to 0 ^oC, brown precipitates was collected by filtration and dried under vacuo to give 28 as a brown solid (111 mg, 0.34 mmol, 38 %). EI-MS m/z (%): 320.9 (45) [M⁺].

6-(((4-ethynylphenyl)amino)methyl)pteridine-2,4-diamine (37): Reaction was carried out under N2 protection, to a solution of 6-(bromomethyl)pteridine-2,4-diamine 24 (500 mg, 1.96 mmol) in 40 ml DMA, 4-ethynylaniline 36 (300 mg, 2.5 ml) was added, the reaction mixture was stirred at r.t. for 48 h, 50 ml H2O was added and cooled to r.t. Brown precipitates were filtrated and dried under vacuo to give 37 as a brown solid (206 mg, 0.71 mmol, 38 %). EI-MS m/z (%): 292.1 (100) [M+H] ⁺.

(1-benzyl-1H-1,2,3-triazol-4-yl)methyl 4-(((2,4-diaminopteridin-6-yl)methyl)amino)benzoate (32): To a suspension of prop-2-yn-1-yl 4-(((2,4-diaminopteridin-6-yl)methyl)amino)benzoate 27 (100 mg, 0.28 mmol), (azidomethyl)benzene 31 (57 mg, 0.43 mmol) and tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine (TBTA) (7.5 mg, 0.05 mmol) in CH2Cl2/MeOH/H2O (6 : 10 : 3 v/v, 6 ml) was added CuSO4 (22.8 mg, 0.14 mmol) and ascorbic acid (50.4 mg, 0.28 mmol). The reaction was left to stirred under N2 at 80 °C for 12 h, upon completion, adjust pH to 3 by adding 1N HCl, the precipitate was collected by filtration and dried under vacuo to give 32 as a brown solid (97 mg, 0.2 mmol, 70 %). EI-MS m/z (%): 483.4 (100) [M+H] ⁺.

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethoxy))] (30): To a suspension of 19a (638 mg, 0.98 mmol), phenylacetylene 29a (100 mg, 0.98 mmol) and tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine (TBTA) (26.0 mg, 0.05 mmol) in CH2Cl2/MeOH/H2O (6 : 10 : 3 v/v, 6 ml) was added CuSO4 (78 mg, 0.49 mmol) and ascorbic acid (1072 mg, 0.98 mmol). The reaction was left to stirred under N2 at 80°C for 12 h and monitored by TLC. Upon completion, the reaction mixture was washed by H2O (2 × 30 ml) and extracted by CH2Cl2 (30 ml), the organic phase was washed with brine and separated then dried over MgSO4, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE/EA = 3 : 1 then DCM/MeOH = 10 : 1) to give 30 as a red solid (650 mg, 0.88 mmol, 90 %). M.p.: Decomposition 175 °C; IR absorptions (cm^-1, ATR): 2909, 1673, 1617, 1473, 1363, 1245, 1120, 1047, 947, 850, 746; ¹H NMR (d6-acetone, 400 MHz): δ 7.64 (s, 2H, Hpyr), 7.56 (s, 1H, Htriazole), 7.34-7.40 (m, 3H, Har), 7.26-7.29 (m, 2H, Har), 6.75 (d, J = 1.8 Hz, 2H, Har), 6.63 (d, J = 1.8 Hz, 2H, Har), 5.54 (s, 2H, N-NCH2), 5.36 (s, 2H, OCH2), 5.25 (d, J = 14.2

Hz, 2H, CarCH2), 3.35 (d, J = 9.3 Hz, 2H, NCH2), 3.11 (d, J = 14.2 Hz, 2H, CarCH2), 2.73 (s, 6H,

[Ti(Ph^2,4-MeN^Me)2(dipic4(2(4((8R,9S,13S,14S,17S)3,17dihydroxy13methyl7,8,9,11,12,13,14,15,16,17decahydro6H cyclo pen -ta[α]phenant hren -17-yl) -1H-1,2,3-triazol-1-yl)ethoxy))] (59a): To a suspension of 19a (400 mg, 0.6 mmol), ethinylestradiol 58 (199.8 mg, 0.67 mmol) and tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine (TBTA) (16.3 mg, 0.03 mmol) in CH2Cl2/MeOH/H2O (6 : 10 : 3 v/v, 20 ml) was added a aqueous solutions of CuSO4 (48 mg, 0.31 mmol, 0.25 ml H2O) and ascorbic acid (107 mg, 0.6 mmol, 0.25 ml H2O). The reaction was left to stirred under N2 at 80 °C for 12 h and monitored by TLC, upon completion, the reaction mixture was washed by H2O (2 × 30 ml) and extracted by CH2Cl2 (30 ml), the organic phase was washed with brine and separated then dried over MgSO4, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE/EA = 3 : 1 then DCM/MeOH = 10 : 1) to give 59a as a red solid (229 mg, 0.24 mmol, 40 %). M.p.:

127.8 (Car), 127.4 (Car), 126.2 (Car), 124.2 (Car), 123.0 (Car), 114.9 (Car), 112.6 (Car), 110.8 (Car), 81.6 (HOC), 68.6 (OCH2), 63.2 (CarCH2), 53.4 (NCH2), 48.8 (Cal), 48.1 (Cal), 47.1 (NCH3), 46.1(NCH2), 43.6 (Cal), 39.8 (Cal), 37.5(Cal), 33.0 (Cal), 31.4 (Cal), 27.4 (Cal), 26.3 (Cal), 23.6 (Cal), 22.4 (Cal), 19.8 (CarCH3), 15.1(CarCH3), 14.0 (Cal), 13.5 (Cal); HRMS (ESI-TOF) m/z Calcd for C51H61N6O9Ti [M+H]⁺ : 949.3974. Found 949.3927.

 

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(2-(4-((8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclo penta[α] phenanthren-17-yl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl))] (59b): Following the same procedure as for 59a with 19b (400 mg, 0.5 mmol), ethinylestradiol 58 (191.1 mg, 0.64 mmol) and tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine (TBTA) (15.5 mg, 0.03 mmol), CuSO4 (46.5 mg, 0.29 mmol, 0.25 ml H2O) and ascorbic acid (103.1 mg, 0.58 mmol, 0.25 ml H2O) in CH2Cl2/MeOH/H2O (6 : 10 : 3 v/v, 20 ml) for 19 h to give 59b as a red solid (316 mg, 0.31 mmol, 55 %). M.p. 217-219 ^oC; IR absorptions (cm

[Ti(Ph^2,4-MeN^Me)2(dipic4-(2-(2-(4-((8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclo penta[α] phenanthren-17-yl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl))] (59b): Following the same procedure as for 59a with 19b (400 mg, 0.5 mmol), ethinylestradiol 58 (191.1 mg, 0.64 mmol) and tris(1-benzyl-1H-1,2,3-triazol-4-yl)methylamine (TBTA) (15.5 mg, 0.03 mmol), CuSO4 (46.5 mg, 0.29 mmol, 0.25 ml H2O) and ascorbic acid (103.1 mg, 0.58 mmol, 0.25 ml H2O) in CH2Cl2/MeOH/H2O (6 : 10 : 3 v/v, 20 ml) for 19 h to give 59b as a red solid (316 mg, 0.31 mmol, 55 %). M.p. 217-219 ^oC; IR absorptions (cm

Im Dokument Functionalization and in vitro study of cytotoxic salan titanium(IV)-bis-chelates (Seite 99-155)