Syntheses and Applications of (Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts

We herein report our efforts to obtain a new class of systematically modified bifunctional (thio)urea-containing quaternary ammonium salts based on easily obtainable chiral backbones. Among the different classes of catalysts that were successfully synthesized, those based on trans-1,2-cyclohexane diamine were found to be the most powerful for the asymmetric α-fluorination of β-keto esters. Selectivities up to 93:7 could be obtained by using only 2 mol-% of the optimized catalyst. The importance of the bifunctional nature of these catalysts was demonstrated by control experiments using simplified monofunctional catalyst analogues, which gave almost racemic product only.


General Information:
1 H-and 13 C-NMR spectra were recorded on a Bruker Avance III 300 MHz spectrometer and on a Bruker Avance III 700 MHz spectrometer with TCI cryoprobe. All NMR spectra were referenced on the solvent peak. High resolution mass spectra were obtained using an Agilent 6520 Q-TOF mass spectrometer with an ESI source and an Agilent G1607A coaxial sprayer. All chemicals were purchased from commercial suppliers and used without further purification unless otherwise stated. All reactions were performed under an Ar-atmosphere.
Starting β-ketoesters were either purchased from commercial suppliers or prepared according

General Syntheses of Catalysts 1p -1r:
Step 1: A solution of the quaternary ammonium salt 9 and trifluoroacetic acid (10 eq.) in DCM (10 mL / mmol) was stirred at r.t. for 2 h. After evaporation to dryness, the crude amine was directly subjected to the final coupling step.
Step 2: A mixture of the amine, R 2 NCX (1.5 eq.), and K 2 CO 3 (3 eq.) in DCM (10 mL / mmol) was stirred at r.t. for 8-18 h. After filtration and evaporation to dryness, the crude product was purified by column chromatography (DCM:MeOH, 40:1 → 10:1) to obtain catalysts 1 in the reported yields. Step 2: K 2 CO 3 (345 mg, 2.5 mmol, 5 eq) was added to a solution of mono-Boc-protected diamine (167mg, 0.5 mmol) in 5 ml AcN. After the addition of 310 µl (5 mmol, 10 eq) methyl S 16 iodide the suspension was stirred for 1 d. After evaporation of excess methyl iodide and AcN, the residue was dissolved in DCM and filtered to give Boc-protected ammonium intermediate as an oily residue in quantitative yield. The product was used without further purification.

Synthesis of Tartaric Acid-Based Catalysts 4:
Syntheses of 16a: Step 1: A solution of 14 (1.43 g, 8.9 mmol) (prepared according to literature 7 ) in DCM (38 mL) was cooled to 0 °C. A solution of allylchloroformate (385 µL, 0.4 eq.) in DCM (10 mL) was added dropwise over 2 h. The mixture was stirred for further 16 h on an ice bath. After extraction with EtOAc/Na 2 CO 3 (sat.) the organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to dryness to give a 2:1 mixture of 15 and the di-Alloc-protected amine which was used directly for the next step.
Step 2: A mixture of crude

Asymmetric α-Fluorination:
General procedure for the α-fluorination of β-ketoesters: Reactions were usually carried out using 0.1 -0.5 mmol of the ketoester. Aqueous K 3 PO 4 (2M, 2 eq.) was added to a mixture of ketoester and catalyst 1o (2 mol%) in m-xylene (20 mL / mmol ketoester) and the mixture was cooled to -10 °C. NFSI was added portion-wise over 2 h and the mixture was heavily stirred for another 10 h at -10 °C (Ar-atmosphere). The reaction was quenched by addition of NH 4 Cl (sat) and the mixture was extracted with CH 2 Cl 2 . After drying over Na 2 SO 4 , and evaporation to dryness, the product was purified by silica gel column chromatography (heptanes:EtOAc = 20:1) to give the products in the reported yields.