Asymmetric Henry Reaction of 2-Acylpyridine N-Oxides Catalyzed by a Ni-Aminophenol Sulfonamide Complex: An Unexpected Mononuclear Catalyst

The asymmetric Henry reaction of 2-acylpyridine N-oxide remains a challenge as N-oxides generally act as competitive catalyst inhibitors or displace activating ligands. A novel variable yield (up to 99%) asymmetric Henry reaction of 2-acypyridine N-oxides catalyzed by a Ni-aminophenol sulfonamide complex with good to excellent enantioselectivity (up to 99%) has been developed. Mechanistic studies suggest that the unique properties of the electron-pairs of N-oxides for complexation with Ni makes the unexpected mononuclear complex, rather than the previously reported dinuclear complex, the active species.


Catalytic Asymmetric Henry Reaction
In the preliminary study, the complexes prepared in situ from L1 (Figure 1) and different metal salts in a 1/2 molar ratio (for examples in asymmetric bimetallic catalysis based on aminophenol sulfonamide ligands, see [44][45][46]) were used to catalyze the asymmetric Henry reaction of 2-acylpyridine N-oxide and nitromethane, and Ni(OAc) 2 gave the best results (see the supplementary materials for details).However, in the subsequent molar ratio investigation of metal/ligand, it was found that 1/1 gave better enantioselectivity than 2/1 (Table 1, entry 1 vs. entry 3).

Catalytic Asymmetric Henry Reaction
In the preliminary study, the complexes prepared in situ from L1 (Figure 1) and different metal salts in a 1/2 molar ratio (for examples in asymmetric bimetallic catalysis based on aminophenol sulfonamide ligands, see [44][45][46]) were used to catalyze the asymmetric Henry reaction of 2acylpyridine N-oxide and nitromethane, and Ni(OAc)2 gave the best results (see the supplementary materials for details).However, in the subsequent molar ratio investigation of metal/ligand, it was found that 1/1 gave better enantioselectivity than 2/1 (Table 1, entry 1 vs. entry 3).d The absolute configuration of the major product was inverse compared with the others by the analysis of HPLC.
The ratio was investigated intensively with the results summarized in Table 1 (entries 1-7).It was found that increased metal ratio could increase the reactivity (Table 1, entries 1 and 2 vs. 3-7)

Catalytic Asymmetric Henry Reaction
In the preliminary study, the complexes prepared in situ from L1 (Figure 1) and different metal salts in a 1/2 molar ratio (for examples in asymmetric bimetallic catalysis based on aminophenol sulfonamide ligands, see [44][45][46]) were used to catalyze the asymmetric Henry reaction of 2acylpyridine N-oxide and nitromethane, and Ni(OAc)2 gave the best results (see the supplementary materials for details).However, in the subsequent molar ratio investigation of metal/ligand, it was found that 1/1 gave better enantioselectivity than 2/1 (Table 1 The ratio was investigated intensively with the results summarized in The ratio was investigated intensively with the results summarized in Table 1 (entries 1-7).It was found that increased metal ratio could increase the reactivity (Table 1, entries 1 and 2 vs. 3-7) and excess ligands provided higher ee (Table 1, entries 4-7 vs. 1-3).The best ratio of metal/ligand was 1/1.1 with 86% yield and 85% ee.We speculate that the excess metal could increase the amount of Ni/N-oxide complexes and Ni 2 /L1 complexes [45], both of which are higher active species with lower selectivity.At the ratio of 1/1.1, a 1/1 coordination complex of Ni/L1 could be generated to the greatest extent.After the screening of benzenesulfonyl moiety, L2 was found to be the most promising ligand (Table 1, entries 8-14; Figure 1).The corresponding results of L9-L11 (Table 1, entries 15-17; Figure 1) showed both of the phenolic hydroxyl group and sulphonamide group played a key role in achieving high ee.
Next, different bases were examined, with the results shown in Table 2.The tertiary and secondary amines investigated showed excellent activity, except for N-methylmorpholine.The substituent size at the nitrogen atoms plays a key role in the selectivity and N,N-dicyclohexyl-methylamine gave the best results (Table 2, entry 2).On the other hand, the addition order of 2-acylpyridine N-oxide and nitromethane had an effect on the enantioselectivity and the addition of 2-acylpyridine N-oxide first was conducive to high ee (Table 2, entries 2 vs. 8).and excess ligands provided higher ee (Table 1, entries 4-7 vs. 1-3).The best ratio of metal/ligand was 1/1.1 with 86% yield and 85% ee.We speculate that the excess metal could increase the amount of Ni/N-oxide complexes and Ni2/L1 complexes [45], both of which are higher active species with lower selectivity.At the ratio of 1/1.1, a 1/1 coordination complex of Ni/L1 could be generated to the greatest extent.After the screening of benzenesulfonyl moiety, L2 was found to be the most promising ligand (Table 1, entries 8-14; Figure 1).The corresponding results of L9-L11 (Table 1, entries 15-17; Figure 1) showed both of the phenolic hydroxyl group and sulphonamide group played a key role in achieving high ee.
Next, different bases were examined, with the results shown in Table 2.The tertiary and secondary amines investigated showed excellent activity, except for N-methylmorpholine.The substituent size at the nitrogen atoms plays a key role in the selectivity and N,N-dicyclohexylmethylamine gave the best results (Table 2, entry 2).On the other hand, the addition order of 2acylpyridine N-oxide and nitromethane had an effect on the enantioselectivity and the addition of 2acylpyridine N-oxide first was conducive to high ee (Table 2, entries 2 vs. 8).N,N-Dicyclohexylmethylamine.e N-methylmorpholine.f Dicyclohexylamine.g Different reaction operation: the order of addition of nitromethane and 2-acylpyridine N-oxide was reversed.In the standard operation, 2-acylpyridine N-oxide was added to the complex prepared in situ for 10 min before the addition of nitromethane.For the detailed standard operation, see the experimental section.
With the optimized reaction conditions in hand (for more detailed results of optimization studies, such as solvents effect, substrate concentration and the amount of nitromethane, see the supplementary materials), the substrate scope was explored.The results are summarized in Table 3.The presence of 4-and 5-substituents (Me or Cl) on the pyridine ring did not affect the high activity and excellent selectivity (Table 3, entries 2, 3 and 5).The substituent of 5-Br provided an unexpectedly low yield with a good ee (Table 3, entry 6).The 6-position substituent on the pyridine ring greatly impairs the ee (Table 3, entry 4).The reaction between 3-methyl substituted substrate and CH3NO2 did not take place.This catalytic system is still effective for ethyl and propyl ketones (Table 3, entrys 7 and 8).The aromatic ketone afforded product 2i in good ee, albeit with moderate yield (Table 3 e N-methylmorpholine.f Dicyclohexylamine.g Different reaction operation: the order of addition of nitromethane and 2-acylpyridine N-oxide was reversed.In the standard operation, 2-acylpyridine N-oxide was added to the complex prepared in situ for 10 min before the addition of nitromethane.For the detailed standard operation, see the experimental section. With the optimized reaction conditions in hand (for more detailed results of optimization studies, such as solvents effect, substrate concentration and the amount of nitromethane, see the supplementary materials), the substrate scope was explored.The results are summarized in Table 3.The presence of 4-and 5-substituents (Me or Cl) on the pyridine ring did not affect the high activity and excellent selectivity (Table 3, entries 2, 3 and 5).The substituent of 5-Br provided an unexpectedly low yield with a good ee (Table 3, entry 6).The 6-position substituent on the pyridine ring greatly impairs the ee (Table 3, entry 4).The reaction between 3-methyl substituted substrate and CH 3 NO 2 did not take place.This catalytic system is still effective for ethyl and propyl ketones (Table 3, entrys 7 and 8).The aromatic ketone afforded product 2i in good ee, albeit with moderate yield (Table 3, entry 9).

Mechanistic Studies of Ni-Aminophenol Sulfonamide Complex
The control experiments (Table 1, entries 1-7) indicated that the mononuclear system is important for high stereoselectivity and the addition of 2-acylpyridine N-oxide first was conducive to high ee (Table 2, 2 and 8).To gain some insight into the mechanism, the ESI-MS studies of the mixture of Ni(OAc)2/L2 (1:1.1) and 1a were carried out (Figure 2, for more details, see supplementary materials).The spectrum displayed ions at m/z 1179, 1316, 1453, 1590, which corresponded to C1-C4 (Figure 3).This confirms the unique properties of the electron-pairs of N-oxides for complexation with Lewis acids [47][48][49].In addition, there was a linear relationship between the enantiomeric excess of the Ni(OAc)2-L2 (1:1.1)catalyst and product 2a (Figure 4).These results suggested that the active species in the present reaction would be a monomeric NiOAc-L2 catalyst.The proposed working model was illustrated in Figure 5 to rationalize the asymmetric induction.The keto functionality is coordinated to Ni in the more Lewis acidic equatorial position for maximal activation [50,51], whereas the nitronate generated by the base is positioned by the hydrogen bonding.

Mechanistic Studies of Ni-Aminophenol Sulfonamide Complex
The control experiments (Table 1, entries 1-7) indicated that the mononuclear system is important for high stereoselectivity and the addition of 2-acylpyridine N-oxide first was conducive to high ee (Table 2, 2 and 8).To gain some insight into the mechanism, the ESI-MS studies of the mixture of Ni(OAc) 2 /L2 (1:1.1) and 1a were carried out (Figure 2, for more details, see supplementary materials).The spectrum displayed ions at m/z 1179, 1316, 1453, 1590, which corresponded to C1-C4 (Figure 3).This confirms the unique properties of the electron-pairs of N-oxides for complexation with Lewis acids [47][48][49].In addition, there was a linear relationship between the enantiomeric excess of the Ni(OAc) 2 -L2 (1:1.1)catalyst and product 2a (Figure 4).These results suggested that the active species in the present reaction would be a monomeric NiOAc-L2 catalyst.The proposed working model was illustrated in Figure 5 to rationalize the asymmetric induction.The keto functionality is coordinated to Ni in the more Lewis acidic equatorial position for maximal activation [50,51], whereas the nitronate generated by the base is positioned by the hydrogen bonding.

Mechanistic Studies of Ni-Aminophenol Sulfonamide Complex
The control experiments (Table 1, entries 1-7) indicated that the mononuclear system is important for high stereoselectivity and the addition of 2-acylpyridine N-oxide first was conducive to high ee (Table 2, 2 and 8).To gain some insight into the mechanism, the ESI-MS studies of the mixture of Ni(OAc)2/L2 (1:1.1) and 1a were carried out (Figure 2, for more details, see supplementary materials).The spectrum displayed ions at m/z 1179, 1316, 1453, 1590, which corresponded to C1-C4 (Figure 3).This confirms the unique properties of the electron-pairs of N-oxides for complexation with Lewis acids [47][48][49].In addition, there was a linear relationship between the enantiomeric excess of the Ni(OAc)2-L2 (1:1.1)catalyst and product 2a (Figure 4).These results suggested that the active species in the present reaction would be a monomeric NiOAc-L2 catalyst.The proposed working model was illustrated in Figure 5 to rationalize the asymmetric induction.The keto functionality is coordinated to Ni in the more Lewis acidic equatorial position for maximal activation [50,51], whereas the nitronate generated by the base is positioned by the hydrogen bonding.

General Information
Commercial reagents were used as purchased.NMR spectra (600 MHz, Bruker, Karlsruhe, Germany) were recorded in the deuterated solvents as stated, using residual non-deuterated solvent signals as the internal standard.High resolution mass spectra were recorded with a Bruker Solari XFT-ICR-MS system.The enantiomeric excess (ee) was determined by HPLC analysis (LC-16,

General Information
Commercial reagents were used as purchased.NMR spectra (600 MHz, Bruker, Karlsruhe, Germany) were recorded in the deuterated solvents as stated, using residual non-deuterated solvent signals as the internal standard.High resolution mass spectra were recorded with a Bruker Solari XFT-ICR-MS system.The enantiomeric excess (ee) was determined by HPLC analysis (LC-16,

General Information
Commercial reagents were used as purchased.NMR spectra (600 MHz, Bruker, Karlsruhe, Germany) were recorded in the deuterated solvents as stated, using residual non-deuterated solvent signals as the internal standard.High resolution mass spectra were recorded with a Bruker Solari XFT-ICR-MS system.The enantiomeric excess (ee) was determined by HPLC analysis (LC-16,

General Information
Commercial reagents were used as purchased.NMR spectra (600 MHz, Bruker, Karlsruhe, Germany) were recorded in the deuterated solvents as stated, using residual non-deuterated solvent signals as the internal standard.High resolution mass spectra were recorded with a Bruker Solari XFT-ICR-MS system.The enantiomeric excess (ee) was determined by HPLC analysis (LC-16, Shimadzu, Suzhou, China) using the corresponding commercial chiral column as stated in the experimental procedures at 23 • C with UV detector.Optical rotations were measured on a commercial polarimeter (Autopol I, Rudolph, Hackettstown, NJ, USA) and are reported as follows: [α] D T (c = g/100 mL, solvent).The absolute configuration of 2a-2d, 2f, 2g and 2i were assigned by comparison with the sign of optical rotation value found in the literature.The absolute configuration of 2e and 2h was determined by analogy.

Conclusions
We have developed a new mononuclear Ni-aminophenol sulphonamide complex for the asymmetric Henry reaction of 2-acylpyridine N-oxides.The simple experimental protocol affords various optically active pyridine-containing β-nitro tert-alcohols in variable yield (up to 99%) with good to excellent enantioselectivity (up to 99%).Mechanistic studies suggested that the unique properties of the electron-pairs of N-oxides for complexation with Ni makes the unexpected mononuclear complex, rather than the previously reported dinuclear complex, the active species.

Figure 3 .
Figure 3.The speculated structures of Ni/L2/1a according to the ESI-MS analysis.

Figure 4 .Figure 5 .
Figure 4. Linear relationship between ee of L2 and ee of product 2a.

Figure 3 .
Figure 3.The speculated structures of Ni/L2/1a according to the ESI-MS analysis.

Figure 3 .
Figure 3.The speculated structures of Ni/L2/1a according to the ESI-MS analysis.

Figure 4 .Figure 5 .
Figure 4. Linear relationship between ee of L2 and ee of product 2a.

Figure 4 .
Figure 4. Linear relationship between ee of L2 and ee of product 2a.

Figure 3 .
Figure 3.The speculated structures of Ni/L2/1a according to the ESI-MS analysis.

Figure 4 .Figure 5 .
Figure 4. Linear relationship between ee of L2 and ee of product 2a.

Figure 5 .
Figure 5.The proposed working model.

Table 1 .
Effect of the metal/ligand ratio and the ligand structure in the asymmetric Henry reaction a .

Table 1 .
Effect of the metal/ligand ratio and the ligand structure in the asymmetric Henry reaction a .

Table 1 .
, entry 1 vs. entry 3).Effect of the metal/ligand ratio and the ligand structure in the asymmetric Henry reaction a .

1a 2a Entry Ni(OAc)2 (x) Ligand (y) x/y Yield (%) b ee (%) c
b Isolated yield.cDetermined by chiral HPLC.dThe absolute configuration of the major product was inverse compared with the others by the analysis of HPLC.

Entry Ni(OAc) 2 (x) Ligand (y) x/y Yield (%) b ee (%) c
b Isolated yield.c Determined by chiral HPLC.d The absolute configuration of the major product was inverse compared with the others by the analysis of HPLC.

Table 2 .
Further optimization of the reaction a .

Table 2 .
Further optimization of the reaction a .

Table 3 .
Substrate scope for the asymmetric Henry reaction a .

Table 3 .
Substrate scope for the asymmetric Henry reaction a .

Table 3 .
Substrate scope for the asymmetric Henry reaction a .
b Isolated yield.c Determined by chiral HPLC.