Effective asymmetric Michael addition of acetone to nitroalkenes promoted by chiral proline amide-thiourea bifunctional catalysts

A series of secondary amine-thiourea catalysts 1a-1d derived from L -proline and chiral diamine were prepared and successfully applied to the Michael addition of acetone to trans -nitroalkenes in excellent yields (up to 99%) and enantioselectivities (44-91% ee)


Introduction
Michael addition is one of the most important reactions in carbon-carbon bond formation.2] Over the past years, various efficient chiral organocatalysts have been developed for the enantioselective Michael addition of aldehydes, 3 ketones 4 and 1,3-dicarbonyl compounds 5 to nitroalkenes.In 2005, Jacobsen 6 first reported the highly efficient primary amine-thiourea catalyzed addition of ketone to nitroalkenes in high enantioselectivities across a broad range of substrates, as well as high diastereo-and regioselectivities.In 2008, Zhao 7 reported that the assemblies of simple -amino acids and quinine derived tertiary amine-thioureas can serve as excellent asymmetric catalysts for such an addition.Tsogoeva 8 has developed imidazole based thioureas which exhibit good enantioselectivities in the same addition of acetone to several nitroalkenes.Although excellent results have been achieved by these systems, few excellent protocols of asymmetric Michael addition of acetone to nitroalkenes were reported. 9The successful design of a simple and highly effective chiral catalyst for the Michael addition of acetone to nitroolefins with excellent enantioselectivities is still a challenging task.
Recently, bifunctional activations, which simultaneously activate both acceptors and donors, have been regarded as an important strategy in asymmetric small molecular catalysis. 10As a typical and effective activation model, chiral thiourea catalysts have been widely used due to their effective activation of carbonyl and nitro groups through double hydrogen-bonding interactions, 11 and second amine, especially L-proline and L-prolic amides, have been well identified as powerful catalysts to activate aldehydes or ketones via enamine or imine transition state. 12Held the concept of bifunctional activations, we considered a kind of catalysts bearing both L-proline and thiourea functional moieties linked by a suitable chiral linker and expected they may simultaneously activate both a nucleophile and an electrophile in the same asymmetric reaction.Typically, the chiral proline amide-thiourea catalysts 1a-1d (Figure 1) in our hands, synergistically combining two catalytic sites of chiral thiourea and L-prolic amide skeleton didn't draw enough attention. 13We excepted that these bifunctional catalysts may catalyze the asymmetric Michael addition of acetone to nitroalkenes and the reactivity and enantioselectivity may be enhanced by double activation, mutual stereo-compatibility and chiral recognition.As a part of our continuing interests in asymmetric synthesis, [14][15] herein, we wish to report the first example of these chiral proline amide-thiourea bifunctional catalysts promoted enantioselective Michael addition of acetone to nitroalkenes in good yields and enantioselectivities.The whole scheme, strategies for these catalysts are illustrated in Figure 1.

Results and Discussion
Chiral catalysts 1a-1d may be similarly prepared as reported procedures. 13To determine the optimal asymmetric reaction conditions, Michael addition of acetone to trans-nitrostyrene at room temperature was selected as the model reaction and chiral catalysts 1a-1d were initially screened, and the results were shown in Table 1.All catalysts of 1a-1d afforded good yields (65-89%), whereas in disappointing enantioselectivities (5-36% ee).Comparatively, catalysts 1a and 1c gave better yields and enantioselectivities (Table 1, entries 1 vs 2, 3 vs 4).It is probably due to the compatibility of the two catalytic chiral centers.The less incompatible chiral centers in 1b and 1d probably exert no synergic or negative effects on the enantioselectivity.Catalysts 1a, bearing a (R, R)-linker, affording the desired products in 36% ee, was chosen for further optimization.With the selected catalyst 1a, effects of solvents and additives were investigated to optimize the reaction conditions.As shown in Table 2, the yields and enantioselectivities were highly variable in different solvents.In polar protic solvents such as CH3OH, almost no desired product was observed after 72 hours (Table 2, entry 1), whereas in polar aprotic solvents such as DMF, the Michael reaction proceeded smoothly and gave the desired product in 88% yield and <5% ee (Table 2, entry 2).Less polar solvents were better for this transformation and the Michael adducts were obtained in excellent yield (83-96%) and moderate to good enantioselectivities (23-81% ee) (Table 2, entries 3-11).When Et2O or THF as solvent, the reaction was performed smoothly and relatively high yields and moderate to good enantioselectivities were obtained (Table 2, entries 8, 10).In particular, the highest enantioselectivity (81% ee) was achieved when Et2O used as solvent (Table 2, entry 10).To further increase the enantioselectivity, a series of additives such as H2O, acids and bases were evaluated.15 mol% water gave racemic product (Table 2, entry 12) and 2 eq water afforded only 14% ee (Table 2, entry 13).The addition of acids (Table 2, entries 15, 16, 18-21) and bases (Table 2, entries 22-25) could not gave improved results.The influence of temperature was also investigated.Lower temperature can slightly increase the enantioselectivity (91% ee), while dramatically decrease the reaction rate (21% yield, Table 2, entry 17).Through extensive screening, the optimized reaction conditions were found to be 20 mol % of catalyst 1a, 20 eq.acetone, Et2O as solvent at room temperature.e 200 mol % additive loading.f The reaction was performed at -20 o C.

Conclusions
In conclusion, we successfully applied the chiral proline amide-thiourea bifunctional catalysts 1a-1d with two catalytic sites of chiral thiourea and L-prolic amide skeleton to catalyze the Michael addition of acetone to nitroalkenes with excellent yields (up to 99 %) and enantioselectivities (up to 91% ee) for a variety of aryl and hetereoaryl nitroalkenes.Further applications of the newly developed catalysts and related analogues in other catalytic reactions are currently underway.

Experimental Section
General Procedures. 1 H NMR and 13 C NMR spectra were recorded on a Bruker NMR (300 MHz).Chemical shifts of 1 H and 13 C were given in δ relative to tetramethylsilane (TMS).
Coupling constant J was given in Hz.Enantioselectivities were determined by HPLC analysis on chiral Whelk-01 or Chiralpak OD-H columns.IR spectra were recorded on a ThermoFisher Nicolet 6700 FTIR spectrometer on a KBr beamsplitter.High-resolution mass spectra were obtained with the microTOF-Q II10203 mass spectrometer.

Typical procedure for the preparation of catalyst 1
To a solution of chiral amine 5 (10.7 mmol, 1.0 eq) in CH2Cl2 (30 mL), was added 3,5bis(trifuoromethyl)phenyl isothiocyanate (2.33g, 8.6 mmol, 0.8 eq).The reaction mixture was stirred at 0 o C for 20 hours.After the reaction was completed (monitored by TLC), the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent PE:EtOAc = 8:1 to EtOAc) to afford pure products 6 as a light yellow solid.The solution of (S)-Boc-proline (3.00g, 14.1 mmol, 1.1 eq), TEA (1.41g, 14.3 mmol, 1.1 eq) in THF (40 mL) was stirred for 1 h at 0 o C, and ethyl chloroformate (1.25mL, 14.3 mmol, 1.1 eq) was added and stirred at 0 o C for 30 min.Compound 6 (13.0 mmol, 1.0 eq) was then added, and the solution was stirred for another 12 h at 0 o C.After the reaction was completed (monitored by TLC), the mixture was filtered, and the organic layer was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent PE:EtOAc = 8:1 to EtOAc) to afford pure products 7.

Typical procedure for the asymmetric Michael addition of acetone to nitroalkenes
Catalyst 1a (0.02 mmol) was added to a stirred solution of acetone 2 (2 mmol) in solvent (0.85 mL) under an atmosphere of air.The resulting solution was stirred for 5 min prior to the addition of nitroolefin 3 (0.1 mmol) and the additive (0.02 mmol).After stirring for the indicated reaction time at room temperature (monitored by TLC), the crude adduct was purified by column chromatography (petroleum ether/ethyl acetate, 10:1).

Table 1 .
The catalyst screening for Michael addition of acetone to trans-nitrostyrenea

Table 3 .
Asymmetric Michael addition of acetone to β-nitroalkenes a b Isolated yield after silica gel chromatography.C Determined by HPLC using Chiral Whelk-01 column or chiralpak OD-H column.