Catalytic enantioselective Henry reaction of α-keto esters, 2-acylpyridines and 2-acylpyridine N-oxides

A pre-prepared Ni–PyBisulidine complex has been developed for the catalytic asymmetric Henry reaction of α-keto esters, 2-acylpyridines and 2-acylpyridine N-oxides. The corresponding β-nitro-α-hydroxy esters were obtained in good to excellent yields (up to 99%) with a high enantiomeric excess (ee) (up to 94%) with a catalyst loading of 1–2 mol%. The desired products of 2-acylpyridines and 2-acylpyridine N-oxides, which were simple methyl ketones, were obtained in medium to excellent yields (up to 94%) with medium to good ee (up to 86%) by using 2 mol% of catalyst.


Introduction
The Henry reaction is one of the important methods for C-C bond formation. 1 The resulting products, b-nitroalcohols, are key intermediates and building blocks for the synthesis of bioactive natural products and pharmaceutical agents. 1 Thus, increasing efforts have been directed towards developing a catalytic asymmetric Henry reaction. 2 Compared with the well developed asymmetric Henry reaction of aldehydes, the asymmetric Henry reaction of ketones with the formation of a quaternary stereogenic center is more challenging because it oen suffers from low reactivity and poor stereoselectivity. 3 Although Tosaki et al. reported the kinetic resolution of racemic derivatives, 4 the catalytic asymmetric Henry reaction of simple ketones is rarely reported. At present, the study mainly focused on reactive substrates such as triuoromethyl ketones, 5 a-keto esters, 6 a-keto amides, 7 a-keto-phosphonates, 8 and glyoxal hydrates. 9 Holmquist et al. expanded the scope of this reaction to 2-acylpyridine N-oxide, simple ketones, for the rst time. 10 Although great progress has been achieved, several factors, including the relatively high catalyst loading (5-20 mol%) or catalyst preparation, limit the use of existing catalytic methods. At the same time, developing new catalysts for the enantioselective Henry reaction of ketones is still necessary. Recently a sulfonylated pyridine bisimidazolidine: nickel-pyridine bisulidine (Ni-PyBisulidine) complex was introduced for the asymmetric hydrophosphonylation of aldehydes. [11][12][13] In this paper, the use of pre-prepared Ni-PyBisulidine complexes for the asymmetric Henry reaction of a-keto esters, 2-acylpyridines and 2-acylpyridine N-oxides with low catalyst loading (down to 1 mol%) is reported.

Results and discussion
The initial studies of the catalytic asymmetric Henry reaction focused on the addition of nitromethane (CH 3 NO 2 ) to methyl phenyloxoacetate in the presence of the complex of chiral PyBisulidine L1 as ligand (Fig. 1 2 -L1] were used as the catalysts, the corresponding products were not detected ( Table 1, entries 6 and 7). Fortunately, the Ni(OAc) 2 -L1 complex could catalyze this reaction smoothly with 83% ee with a 85% yield when the reaction temperature rose to 35 C ( Table 1, entry 8). However, further increasing the reaction temperature did not improve the reactivity (Table 1, entry 9). Aer screening the benzenesulfonyl moiety of the ligands (Table 1, entries 8, [10][11][12], Ni(OAc) 2 -L1 was selected for further optimization which considered the reactivity and economy.
The inuence of the ester group in the substrate was tested next ( Table 2, entries 1-3). The best result in terms of the conversion and enantioselectivity was obtained with the isopropyl ester ( Table 2, entry 3). The pre-prepared complex 14 gave better results than the complex prepared in situ (Table 2,  compare entries 3 and 4).
When the catalyst loading was reduced to 2 mol%, N-methylmorpholine showed a better performance than iPr 2 NEt in terms of enantioselectivity (Table 4, entries 9 and 10). The amount of 4 A MS was screened together with 10 mol% N-methylmorpholine (Table 4, entries [12][13][14]. Under the optimized conditions (at 35 C, in the presence of 2 mol% Ni-L1, 10 mol% N-methylmorpholine, and 150 mg mmol À1 4 A MS in THF), 2ac was obtained with a 92% yield with 93% ee (Table 4, entry 13). The current catalytic system was applied to various a-keto esters (Table 5). In all cases, the reactions were clean and proceeded and gave good to excellent yields with high   enantioselectivities. Aromatic keto esters bearing the electrondonating groups gave smaller yields but the high enantioselectivities were maintained (72-83% yield, Table 5, 2bc-2dc, and 2gc). Aromatic keto esters bearing the electron-withdrawing group gave excellent yields (Table 5, 2ec, and 2ic-2mc) and the catalyst loading could be reduced to 1 mol% with high to excellent yields and high enantioselectivities (Table 5, 2ic-2mc).
The keto esters derived from the bulkier ketone, such as bacetonaphthone, also gave an excellent yield and high enantioselectivity (Table 5, 2fc). The heteroaromatic and alkyl keto esters gave smaller ee values (Table 5, 2hc and 2nb). The conguration of 2ac was identied as R using single crystal diffraction analysis, 15 and the conguration of the other products were inferred to be analogous with that of 2ac. It should be noted that the pre-prepared complex Ni-L1 can be stored in air at 4 C for at least three months without any loss of activity. 16 The Ni-L1 was also used in the asymmetric Henry reaction of 2-acylpyridine N-oxides (Table 6). 17 High yields and good ee were obtained with methyl ketones (Table 6, 4a-4d, 4f). Whereas low ee were obtained with ethyl ketones (Table 6, 4g). The corresponding product of 3-methyl-2-acylpyridine N-oxide was not detected (Table 6, 4e).
Inspired by the research of Tosaki et al. 4 and Holmquist et al. 10 , the Henry reaction of 2-acylpyridines was also investigated (Table 7). 17 In most cases, 50-60% yields and 70-86% ee were obtained with methyl ketones. Racemic products were obtained for ethyl ketones (Table 7, 6g). The Henry reaction of 3methyl-2-acylpyridine did not take place at all. The results were similar to those obtained using 2-acylpyridine N-oxides, indicating that they had similar transition states.
The proposed structure of Ni-L1 on the basis of the related structure of Fe-PyBisulidine complex, 12a the geometry of L1 optimized using Chem3D at the MM2 level ( Fig. 2) and the electrospray ionization-high resolution mass spectrometry (ESI-HRMS) analysis of the complex has previously been reported. 11 To gain some insight into the active species, ESI-HRMS studies of the mixture of Ni-L1 and 3a were carried out. The spectrum displayed ions at m/z 1085.28625 and 1025.26555, which corresponded to C-I and C-II (Fig. 3). It was speculated that the complex C-I or C-II would be the active species. TS1-TS6 are proposed to rationalize the asymmetric induction. As illustrated in Fig. 4, the keto functionality is coordinated to Ni(II) in the more Lewis acidic equatorial position for maximal activation, 18 whereas the nitronate generated by the amine is positioned by the hydrogen bonding. 13g,13h Conclusions A catalytic asymmetric Henry reaction of a-keto esters, 2-acylpyridines and 2-acylpyridine N-oxides, was developed using a Ni-PyBisulidine complex with a low catalyst loading (1-2 mol%). This is the rst example of the direct asymmetric synthesis of tertiary nitro alcohols derived from 2-acylpyridines, which were simple methyl ketones. The catalytic system is tolerant of air and moisture. Further investigations into other versions of asymmetric catalysis are in progress.

General methods
Commercial reagents were used as purchased. High resolution mass spectra were recorded using a Bruker SolariX Fourier- transform ion cyclotron mass spectrometry (FT-ICR-MS) system. Nuclear magnetic resonance (NMR) spectra were recorded in the deuterated solvents [deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD)] as stated, using residual nondeuterated solvent as internal standard. The enantiomeric excess (ee) was determined using high-performance liquid chromatography (HPLC) analysis using the corresponding commercial chiral column as stated in the experimental procedures at 23 C with an ultraviolet detector at 220 nm or 215 nm or 254 nm. Optical rotations were measured on a commercial polarimeter and are reported as follows: [a] T D (c ¼ g per 100 mL solvent).
General procedure for catalytic asymmetric reaction a-Keto esters. The mixture of CH 3 NO 2 (0.2 mL), Ni-L1 (2 mol% or 1 mol%), 4 A MS (30 mg) and N-methylmorpholine (10 mol%) was stirred in THF (0.8 mL) under an air atmosphere at 35 C for 10 min followed by the addition of the a-keto ester (0.2 mmol). The stirring was continued for the reaction time given in Table 5 at 35 C. The residue was puried using silica gel ash column chromatography (petroleum ether/ethyl acetate (EtOAc), 60 : 1-15 : 1) to give the products. The absolute conguration of 2ac was determined using X-ray crystallographic analysis. The absolute conguration of 2ab was assigned by comparison with the sign of optical rotation value found in the literature. 6b The absolute conguration of 2bc-2mc and 2aa was determined by analogy. The absolute conguration of 2nb was assigned by comparison with the sign of optical rotation values found in the literature. 6a,6b,6e,6f,6i 2-Acylpyridine N-oxides. The mixture of CH 3 NO 2 (0.2 mL), Ni-L1 (2 mol%), 4 A MS (30 mg), 2-acylpyridine N-oxides (0.2 mmol) and iPr 2 NH (5 mol%) was stirred in EtOH (0.8 mL) at the temperature specied in Table 6 (À30 C or À40 C) under an air atmosphere for the reaction time identied in Table 6. The residue was puried using silica gel ash column chromatography (petroleum ether/EtOAc, 10 : 1) to give the products. The absolute conguration of 4a-4d and 4f was assigned by comparison with the sign of optical rotation value found in the literature. 10 2-Acylpyridines. The mixture of CH 3 NO 2 (0.2 mL), Ni-L1 (2 mol%), 4 A MS (40 mg), 2-acylpyridine (0.2 mmol) and iPr 2 -NEt (10 mol%) was stirred in THF (0.8 mL) at the temperature specied in Table 7 (À10 C or À20 C) under an air atmosphere for the reaction time indicated in Table 7. The residue was puried using silica gel ash column chromatography (petroleum ether/EtOAc, 10 : 1) to give the products. The absolute conguration of 6a was assigned by comparison with the sign of optical rotation value of its reduced product (7) found in the literature. 10 The absolute conguration of 6b-6d and 6f was determined by analogy.

Conflicts of interest
There are no conicts to declare.