Scheme IV.11. Post-synthetic transformation
IV.4. Experimental Section
IV.4.1. General information: All the reagents were commercial grade and purified according to the established procedures. All the reactions were carried out in oven-dried glassware. The highest commercial quality reagents were purchased and were used without further purification unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) on a 0.25 mm silica gel plates (60F254) visualized under UV illumination at 365 nm. Organic extracts were dried over anhydrous sodium sulfate (Na2SO4).
Solvents were removed using a rotary evaporator under reduced pressure. Column chromatography was performed to purify the crude product on silica gel 60-120 mesh using a mixture of hexane and ethyl acetate as eluent. All the isolated compounds were characterized by 1H, 13C{1H} NMR, HRMS-spectrometric and IR spectroscopic techniques. NMR spectra for all the samples were recorded in deuterochloroform (CDCl3). 1H, 13C{1H} were recorded in 600 (150) or 500 (125) or 400 (100) MHz spectrometer and were calibrated using tetramethylsilane or residual undeuterated solvent for 1H NMR, deuterochloroform for 13C NMR as an internal reference {Si(CH3)4: 0.00 ppm or CHCl3: 7.260 ppm for 1H NMR, 77.230 ppm for 13C{1H} NMR}. 19F NMR was calibrated without any internal standard in CDCl3 in 400 MHz spectrometers. The chemical shifts are quoted in δ units, parts per million (ppm). 1H NMR data is represented as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets), integration and coupling constant(s) J in hertz (Hz). High-resolution mass spectra (HRMS) were recorded on a mass spectrometer using electrospray ionization-time of flight (ESI-TOF) reflection experiments. FT-IR spectra were recorded in KBr or neat and reported in the frequency of absorption (cm-1).
IV.4.2. Crystallographic Information:
(A) Sample Preparation:
The single crystal of compound 1f was prepared by the slow evaporation method for which 10 mg of the compound (1f) was dissolved in 1 mL of DCM in a clean and dry 10 mL glass vial. MeOH (0.5 mL) was added to this solution slowly with a dropper. The mouth of the glass vial was covered with a cap having a small hole and kept it for slow evaporation at
room temperature. Transparent white needle-like single crystals of 1f was obtained after 23 days.
(B) Crystallographic Description of 2-(4-Fluorophenyl)thio)-4,6- diphenylnicotinonitrile (1f):
Diffraction data were collected at 292 K with MoKα radiation (λ = 0.71073 Ǻ) using a Bruker Nonius SMART APEX CCD diffractometer equipped with graphite monochromator and Apex CD camera. The SMART software was used for data collection and for indexing the reflections and determining the unit cell parameters. Data reduction and cell refinement were performed using SAINT1,2 software and the space groups of these crystals were determined from systematic absences by XPREP and further justified by the refinement results. The structures were solved by direct methods and refined by full-matrix least-squares calculations using SHELXTL-973 software. All the non-H atoms were refined in the anisotropic approximation against F2 of all reflections.
1. G. M. Sheldrick, SADABS, 1996, based on the method described in: R. H. Blessing, Acta Crystallogr. 1995, A51, 33–38.
2. SMART and SAINT, Siemens Analytical X-ray Instruments Inc., Madison, WI, 1996.
3. G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112–122.
C24H15FN2S, crystal dimensions 0.35 x 0.31 x 0.29 mm, Mr = 382.44, monoclinic, space group P 21/c, a = 13.2258 (5), b = 8.0745 (3), c = 19.2139 (8) Å, α = 90o, β = 109.317 (1)o, γ = 90o, V = 1936.37 (13) Å3, Z = 4, ρcalcd = 1.312 g/cm3, μ = 0.188 mm-1, F(000)= 792.0, reflection collected / unique = 32809 / 3414, refinement method = full-matrix least-squares on F2, final R indices [I> 2\s(I)]:R1 = 0.0407, wR2 = 0.0973, R indices (all data): R1 = 0.0601, wR2
= 0.1182, goodness of fit = 1.037. CCDC-2201897 for 2-((4-fluorophenyl)thio)-4,6- diphenylnicotinonitrile (1f) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Figure IV.8. ORTEP diagram of 2-((4-fluorophenyl)thio)-4,6-diphenylnicotinonitrile (1f) with 40% ellipsoid probability (CCDC 2201897).
IV.4.3. General Procedure for the Synthesis of 2-(3-oxo-1,3- diphenylpropyl)malononitrile (116):
Compounds 116 were synthesized as per the following the method described in S. Lin, Y. Wei and F. Liang. Chem. Commun., 2012, 48, 9879.
Compounds (1−14) were synthesized by a slight modification of the literature procedure.
To an oven-dried 50 mL round-bottom flask were added chalcone, 1,3-diphenyl-2-propen-1- one (1.04 g, 5.0 mmol.), malononitrile (0.66 g, 10.0 mmol), K2CO3 (1.38 g, 10.0 mmol), and DCE (5 mL). The reaction mixture was stirred at room temperature for 12 h. Then, the reaction mixture was admixed with ethyl acetate (30 mL) and the organic layer was washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product so obtained was purified over a column of silica gel (hexane/ethyl acetate, 9:1) to give pure 2-(3-Oxo-1,3- diphenylpropyl)malononitrile (1) (1.30 g, 95%).
IV.4.4. General Procedure for the Synthesis of 4,6-diphenyl-2- (phenylthio)nicotinonitrile (1a) from 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) and Thiophenol (a):
To an oven-dried 10 mL borosilicate vial were added 2-(3-oxo-1,3- diphenylpropyl)malononitrile (1) (0.25 mmol, 68 mg), eosin Y (3 mol%, 5 mg), and K2CO3
(1 equiv, 34 mg). Then to the reaction mixture benzene thiol (a) (0.5 mmol, 55 mg) in 1 mL of DMSO was added and stirred at room temperature under N2 atmosphere for 3 h, tentatively at a distance of ~12 cm from four 1 W green LEDs. After completion of the reaction (monitored by TLC analysis), the mixture was diluted with water (10 mL) followed by extraction with ethyl acetate (20 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude residue thus obtained was purified by column chromatography over silica gel (60−120 mesh) using hexane and ethyl acetate (98:2) as an eluent to afford the 4,6-diphenyl-2-(phenylthio)nicotinonitrile (1a) in 78% yield. The identity and purity of the product were confirmed by spectroscopic analysis (Scheme S2).
IV.4.5. General Procedure for 5 mmol Scale Reaction for the Synthesis of 4,6-Diphenyl- 2-(phenylthio)nicotinonitrile (1a):
To an oven-dried 50 mL borosilicate round bottom flask, were added 2-(3-oxo-1,3- diphenylpropyl)malononitrile (1) (5 mmol, 1.37 g), eosin Y (3 mol %, 0.135 g), and K2CO3
(1 equiv, 0.966 g). Then to the reaction mixture benzene thiol (a) (10.0 mmol, 1.10 g) in 2 mL of DMSO was added and stirred at room temperature under N2 atmosphere for 3 h, tentatively at a distance of ~12 cm from four 1 W green LEDs. After completion of the reaction (monitored by TLC analysis), the reaction mixture was admixed with ethyl acetate (50 mL) and the organic layer was washed with ice-cooled water (20 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure.
The crude residue thus obtained was purified by column chromatography over silica gel
(60120 mesh) using hexane and ethyl acetate (98:2) as eluent to afford the 4,6-diphenyl-2- (phenylthio)nicotinonitrile (1a) in 64% yield. The identity and purity of the product was confirmed by spectroscopic analysis.
IV.4.6. General Procedure for the Synthesis of 4,6-Diphenyl-2- (phenylthio)nicotinonitrile (1a) in the Presence of Sunlight:
To an oven-dried 25 mL borosilicate round bottom flask, was added 2-(3-oxo-1,3- diphenylpropyl)malononitrile (1) (0.25 mmol, 68 mg), eosin Y (3 mol %, 5 mg), and K2CO3
(1 equiv, 34 mg). Then to the reaction mixture benzene thiol (a) (0.5 mmol, 55 mg), in 1 mL DMSO was added and stirred at room temperature under N2 atmosphere for 56 h, with the surrounding temperature 3035 C. After completion of the reaction (monitored by TLC analysis), the reaction mixture was admixed with ethylacetate (20 mL) and the organic layer was washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude residue thus obtained was purified by column chromatography over silica gel (60-120 mesh) using hexane and ethyl acetate (98:2) as eluent to afford the 4,6-diphenyl-2-(phenylthio)nicotinonitrile (1a) in 70%
yield. The identity and purity of the product was confirmed by spectroscopic analysis.