Microwave irradiation promotes the rapid and efficient reaction of a thiophenol and aryl or heteroaryl halide using a copper or palladium catalyst and a range of ligands, depending upon substrate. Of particular utility is the use of copper(I) iodide (5 mol %) and trans-cyclohexane-1,2-diol as ligand under basic conditions and microwave irradiation to give the corresponding sulfide in high yield. This method for C-S bond formation is applied in the four-step synthesis of the clinical candidate VX-745 in 38% overall yield. The inhibitory activity of VX-745 against p38alpha MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 microM concentration by immunoblot assay.
A new class of thioamide‐substituted cinchona derivatives is reported. A convergent and practical approach was developed to insert the thioamide functional group onto the cinchonidine from readily available dithioesters. These organocatalysts were effective in asymmetric decarboxylative Mannich and protonation reactions of α‐amido‐substituted malonic acid half oxyesters (MAHOs), affording α,β‐ and α‐amino acid derivatives, respectively, in good yields and stereoselectivities.
General information. All reagents were purchased from Acros Organics, Sigma Aldrich, Alfa Aesar, TCI or Fluka and were used without further purification and used as received. Solvents were used in RPE grade without further purification. Anhydrous solvents were obtained from a PURESOLV SPS400 apparatus developed by Innovative Technology Inc.1 H and 13 C NMR spectra were recorded on a Bruker DRX 400 MHz or a Bruker DRX 500 MHz spectrometer. Samples were dissolved in an appropriate deuterated solvent (CDCl3, acetone-d6, MeOD, D2O). The chemical shifts (δ) are expressed in ppm relative to internal tetramethylsilane for 1 H and 13 C nuclei, and coupling constants are indicated in Hz. Abbreviations for signal coupling are as follows: s = singlet; d = doublet; dd = doublet of doublets; t = triplet; q = quartet; quin = quintet; m = multiplet; br = broad signal. To assign the signals to the different proton and carbon atoms, as well as the relative stereochemistry of the cycloadducts, additional 2D NMR experiments (COSY, HSQC, HMBC) and NOESY experiments were performed. Mass spectra were obtained on a GC/MS Saturn 2000 spectrometer. High-resolution mass spectra (HRMS) were performed on Q-TOF Micro WATERS by electrospray ionisation (ESI). Infrared (IR) spectra were recorded with a Perkin Elmer 16 PC FT-IR ATR spectrometer, using the pure product (oil or solid). Thin Layer Chromatography (TLC) was run on pre-coated aluminum plates of silica gel 60 F-254 (Merck). Flash chromatography was performed on silica gel column (Merck silica gel, 40-63 µm) using air pressure. Some compounds (3a and 3b) were known in literature and synthesized as described below.
1)Synthesis of malonatesTo a solution of diethyl 2-[(tert-butoxycarbonyl)amino]malonate (1.0 g, 3.63 mmol, 1 eq) in DMF (50 mL) was added sodium hydride (60% in oil, 0.113 g, 8.61 mmol, 1.3 eq) portionwise. Then, benzyl bromide (0.932 g, 9.94 mmol, 1.5 eq) was added dropwise and the solution was stirred for 24h at room temperature. Water (200 mL) was added and the mixture was extracted with diethyl ether (3*50 mL). The combined organic layers were dried over MgSO4 and the volatiles were removed under reduced pressure. The purification of the crude product by flash chromatography on silica gel with cyclohexane/ethyl acetate (9/1) afforded the diester as colorless oil in 68 % yield (662 mg).
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