Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

A number of upper rim-functionalized calix[4]thiourea cyclohexanediamine derivatives have been designed, synthesized and used as catalysts for enantioselective Michael addition reactions between nitroolefins and acetylacetone. The optimal catalyst 2 with a mono-thiourea group exhibited good performance in the presence of water/toluene (v/v = 1:2). Under the optimal reaction conditions, high yields of up to 99% and moderate to good enantioselectivities up to 94% ee were achieved. Detailed experiments clearly showed that the upper rim-functionalized hydrophobic calixarene scaffold played an important role in cooperation with the catalytic center to the good reactivities and enantioselectivities.


General
All chemicals were used as received without special purification unless stated otherwise. Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light (254 nm). 1

Synthesis of catalysts and characterization data 2.1 Synthesis of isothiocyanato-calix[4]arenes
To a solution of 5a or 5b (1 equiv) in 20 mL DCM, NaOH (3 equiv or 6 equiv, respectively) was added and the resulting mixture was stirred at room temperature for 15 min. Next, phenyl chlorothionocarbonate (1 equiv or 2 equiv respectively) was added slowly in 5 min. After the reaction was complete, the reaction mixture washed with 10% HCl and deionized water. The aqueous layer was extracted with DCM, the combined organic phase was dried over MgSO4 and concentrated to give the crude product, which was purified by flash chromatography on silica gel (eluent with ethyl acetate/hexane 1:100) to afford product 6a or 6b.

Synthesis of catalyst 1
To a solution of chiral (1R,2R)-N-Boc-cyclohexanediamine (0.21 mmol) in DCM (15 mL) was added 6a (0.21 mmol). The reaction mixture was stirred for 0.5 h at room temperature. After removal of the solvent, the crude product was purified by flash chromatography on silica gel (eluent with ethyl acetate/hexane 1:4) to give Boc-protected product. Subsequently, CF 3 COOH (1 mL) and DCM (30 mL) were added, and the mixture was stirred at room temperature for 3 h. After the reaction was complete, the solvent was distilled off. Then, DCM (30 mL) and H 2 O (30 mL) were successively added, and 2.0 mol/L NaOH solution was added dropwise to adjust the pH to 8-9. The aqueous layer was extracted with DCM (3 × 20 mL), the combined organic phase was dried over MgSO 4 and concentrated to give the catalyst 1.

Synthesis of catalyst 2 and 3
To

Synthesis of catalyst 4
To a solution of 4-butoxyaniline (1.0 mmol) in 20 mL DCM, was added NaOH (4.5 mmol) and the resulting mixture was stirred at room temperature for 15 min. Next, phenyl chlorothionocarbonate was added slowly over 5 min. After the reaction was complete, the reaction mixture washed with 10% HCl (2 × 20 mL) and deionized water (2 × 20 mL). The aqueous layer was extracted with DCM (3 × 20 mL), the combined organic phase was dried over MgSO4 and concentrated to give the crude product, which was purified by flash chromatography on silica gel (eluent with ethyl acetate/hexane 1:100) to afford 1-butoxy-4-isothiocyanatobenzene. Then

Synthesis of substrates and characterization data
General procedure: To a stirred solution of the nitroalkene (0.5 mmol) and catalyst 2 (0.025 mmol, 5 mol %) in the mixed solvent of toluene (0.32 mL) and water (0.16 mL) was added acetylacetone (1 mmol). After the reaction was completed (monitored by TLC), the resulting mixture was concentrated and the residue was purified by flash S6 chromatography on silica gel (eluent with ethyl acetate/hexane 1:5 to 1:2) to afford the product. All products had NMR spectra in agreement with published data.