Discovery and enantiocontrol of axially chiral urazoles via organocatalytic tyrosine click reaction

Axially chiral compounds play an important role in areas such as asymmetric catalysis. The tyrosine click-like reaction is an efficient approach for synthesis of urazoles with potential applications in pharmaceutical and asymmetric catalysis. Here we discover a class of urazole with axial chirality by restricted rotation around an N–Ar bond. By using bifunctional organocatalyst, we successfully develop an organocatalytic asymmetric tyrosine click-like reaction in high yields with excellent enantioselectivity under mild reaction conditions. The excellent remote enantiocontrol of the strategy originates from the efficient discrimination of the two reactive sites in the triazoledione and transferring the stereochemical information of the catalyst into the axial chirality of urazoles at the remote position far from the reactive site.

. 1 H NMR o 9. 13          (Aryl isocyanate S1): Et 3 N (0.03 mL, 0.01 equiv) was added to a stirring solution of triphosgene (2.97 g, 10.0 mmol, 0.5 equiv) in dry DCE (50 mL) at 0 . After stirring 5 minutes, aromatic amine (20.0 mmol) in dry DCE (50 mL) was added slowly over 2 h. The reaction mixture was then refluxed and stirred under nitrogen for 4 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to afford S1 as a yellow liquid.
(4-Ar-1-carbethoxysemicarbazide S2): To a solution of methyl carbazate (1.8 g, 20.0 mmol) in anhydrous THF under argon atmosphere, aryl isocyante S1 (20.0 mmol, 1.0 equiv.) was added over 1-2 minutes. The resulting mixture was stirred at room temperature for 1 h. After the reaction completion (monitored by TLC), the white solid product was collected by filtration or by simple evaporation to dryness.
(4-Ar-urazole S3): To a solution of intermediate S2 in methanol, potassium carboxylate (2.0 equiv.) was added and the reaction mixture was refluxed overnight. After the reaction completion (monitored by TLC), the resulting mixture was condensed and re-dissolved with small amount of water. The pH of resulting mixture was adjusted to the range of 3~4 with the drop-wise addition of 1N aqueous HCl. The desired product S3 was collected by simple filtration and washed with cold deionized water prior to drying.
(4-aryl-l,2,4-triazoline-3,5-diones S): N-Bromosuccinimide (20 mmol) was added to an ice-cold suspension of urazoles (10 mmol) in 150 mL of CH 2 C1 2 . After being stirred for 30 min, the resulting red solution was extracted five times with water. The CH 2 Cl 2 layer was then dried over MgSO 4 , filtered, and concentrated under reduced pressure. Purple or dark red solid of various triazolinediones were obtained.

Supplementary Note 2 General procedure for asymmetric synthesis of axially chiral urazoles
In a Schlenk tube 4-aryl-l,2,4-triazoline-3,5-diones 2 (0.12 mmol) and catalyst C7 (5 mol%, 0.005 mmol) were dissolved in Et 2 O (2 mL). The solution was stirred for 10 min at -78 °C before 2-naphthols and phenols 1 (0.10 mmol) were added. The resulting solution was stirred at-78 °C until red color disappeared. After monitored by TLC, the reaction mixture was acidified with 6 N HCl and concentrated. Then the obtained crude material was purified by silica gel column chromatography (CH 2 Cl 2 to CH 2 Cl 2 /Acetone = 10/1) to afford the pure products 3. In some cases, reactions were performed with 20 mol% of catalyst C7 in 2.0 mL solvent, for 3d in DCM at -78 ; 3i and 3j in dry toluene at -40 .
Products 6 were synthesized for NMR spectra of 3 (except 3i and 3j), 6p' for X-ray single crystal diffraction. (Note: The NMR spectra for most of products 3 were displayed very messy and peaks splitting were not clear. Thus, the products 6 were synthesized for better NMR spectra collection.) Potassium carbonate (0.4 mmol, 2.0 equiv) was added to a solution of products 3p (0.2 mmol, 1.0 equiv) and iodomethane (2.0 mmol, 10 equiv) in dioxane (1 mL) at room temperature. The solution was stirred at room temperature for 5 h，then the product 6p was afforded by silica gel flash column chromatography (EtOAc/Hexane = 1/2) with 60% yield.
7f was synthesized for X-ray single crystal diffraction.