English

• 1.   Introduction

  The Henry reaction (nitroaldol reaction) is a very attractive atom economic method for the construction of carbon- carbon bond.^[1~3] The resulting β-nitro alcohols can be easily transformed to β-amino alcohols, α-hydroxy acids, α- hydroxy ketones, and many other building blocks.^[4~6] In fact, the enantioenriched nitroaldol adducts have been re- cognized as an almost unlimited source of valuable synthetic intermediates readily convertible to many biological active compounds.^[7~11] Asymmetric Henry reactions catalyzed by various metal complexes^[12~21] with chiral ligands have been explored quite extensively since the pioneering work of Shibasaki in 1992.^[22] While copper continues to be the preferred metal due to its inexpensive and less toxic nature together with prominent result in most cases.^[23~29] Concerning the chiral ligands, since the pioneering work of J rgensen^{[23, 30]} and Evans, ^[31] bisoxazolines, ^[32~37] bisoxazolidines, ^{[38, 39]} boron-bridged bisoxazolines, ^[40] chiral diamines, ^[41~45] sulfonyldiamine, ^{[26, 46]} thioure^{[47, 48]} and pyridine derivatives, ^[49~51] etc. have been tested in the asymmetric Henry reaction.

  The development of the chiral ligands plays pivotal role in the development of efficient metal-catalyzed asymmetric reactions, and the discovery of novel chiral ligands can open a new era of asymmetric catalysis. Amino alcohols represent one of the most studied classes of chiral ligands/ auxiliaries.^[52~54] They have been used in different forms since the beginning of asymmetric synthesis, including asymmetric Henry reaction.^[55~58] Imidazole derived chiral ionic liquids have been applied successfully as chiral medium or additives to achieve high levels of efficiency in asymmetric reaction. While studies on the application of imidazole derivatives as chiral ligands for the highly enantioselective reactions are still quite rare. Here we report the convenient synthesis of a series of multi-aryl substituted imidazole amino alcohol derivatives and their performance in the asymmetric Henry reaction.

  2.   Results and discussion

  It has been reported that N-substituted imidazole derivatives containing chiral groups could be synthesized efficiently through a “four component-one pot procedure” from the condensation reaction of amino acids, formaldehyde, glyoxal, and ammonia.^{[59, 60]} By carefully choosing the condensation components, we observed that multi-aryl substituted imidazole amino alcohol derivatives 1a~1f carrying appended chiral functionalities could be obtained from the reaction of L-phenylalaninol, dibenzoyl, ammonium acetate and different aromatic aldehydes (Scheme 1).

  Scheme 1

  

  Scheme 1.  Synthesis of multi-aryl substituted imidazole amino alcohol derivatives 1a~1f

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  Because the chiral center did not participate in the condensation directly, there was little risk for the racemization/epimerization of the chiral center.^[61] Figure 1 showed the molecular structure of 1f, demonstrating clearly S configuration of the chiral carbon. The molecular structures of 1b~1c have already been reported to possess S configuration at the chiral carbon.^{[62, 63]} These results confirmed that the chiral carbon in L-phenylalaninol retained the S configuration during the reaction.

  Figure 1

  

  Figure 1.  ORTEP drawing of the molecular structures of ligands 1f at 30% probability displacement ellipsoids. Aromatic, methylene and methyne hydrogen atoms are omitted for clarity

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  Using the addition of nitromethane to benzaldehyde in i-PrOH at room temperature as a model, Cu(OAc)₂•H₂O as copper source, the potential of the chiral imidazole amino alcohol derivatives 1a~1f in asymmetric Henry reaction was tested (Table 1). The results demonstrated that addition of ligands 1a~1f to Cu(OAc)₂ catalyzed Henry reaction improved the yield obviously (Table 1, Entries 1~7). The results obtained with ligand 1c were superior to others in terms of yield and enationselectivity (97% yield, 17% ee), indicating that the coordination ability of the C2-bound substituent on the imidazole affects the yield and enantioselectivity significantly. Other copper sources including CuBr₂, CuBr, CuCl₂, and CuI₂ were tested, and Cu(OAc)₂•H₂O turned out to be the best copper catalyst for the reaction (Table 1, Entries 4, 8~11).

  Table 1

  

  Table 1.  Screening of ligands (1a~1f) and copper source

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  Entrya	Ligand	Copper salts	Yield/%	ee/%
  1	—	Cu(OAc)2•H2O	15	3
  2	1a	Cu(OAc)2•H2O	48	3
  3	1b	Cu(OAc)2•H2O	62	2
  4	1c	Cu(OAc)2•H2O	97	17
  5	1d	Cu(OAc)2•H2O	77	13
  6	1e	Cu(OAc)2•H2O	68	10
  7	1f	Cu(OAc)2•H2O	73	10
  8	1c	CuBr2	56	5
  9	1c	CuBr	10	8
  10	1c	CuCl2	12	11
  11	1c	CuI2	38	6
  a Reagents and conditions: benzaldehyde (1.0 mmol), nitromethane (10.0 mmol), i-PrOH (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

  The effects of catalyst loading, temperature, and solvent were then investigated by running the addition of nitromethane to benzaldehyde in the presence of Cu(OAc)₂•H₂O and ligand 1c as a model. Compared to the blank reaction, addition of 10 mol% of ligand 1c and Cu(OAc)₂•H₂O accelerated the reaction efficiently, improving the yield from 13% to 97% (Table 2, Entries 1~2). Increasing catalyst loading to 20 mol% improved neither yield nor ee value significantly (Table 2, Entries 2~3). Addition of either ligand 1c or Cu(OAc)₂•H₂O alone resulted in very low yields of 22% and 15%, respectively (Table 2, Entries 4~5). These results indicated that the proper catalyst loading is 10 mol% to benzaldehyde. The results from different temperature and solvent showed that lower temperature decelerated the reaction rate with little change on the ee value, while higher temperature resulted in lower ee value (Table 2, Entries 2, 6~7). Among the solvents screened, i-PrOH was superior to EtOH and MeOH (Table 2, Entries 2, 8~9). Other solvents, such as H₂O, DMF, pyridine, toluene, Et₂O, or 1, 4-dioxane lead to decrease in ee value, or both the yield and ee value (Table 2, Entries 10~15).

  Table 2

  

  Table 2.  Effects of catalyst loading, temperature and solvent on the reaction^a

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  Entry	1c/ mol%	Cu(OAc)2•H2O/ mol%	Solvent	Temp.	Yield/%	eeb/%
  1	—	—	i-PrOH	r.t.	13	—
  2	10.0	10.0	i-PrOH	r.t.	97	17
  3	20.0	20.0	i-PrOH	r.t.	98	17
  4	10.0	—	i-PrOH	r.t.	22	5
  5	—	10.0	i-PrOH	r.t.	15	3
  6	10.0	10.0	i-PrOH	0	71	18
  7	10.0	10.0	i-PrOH	50	98	8
  8	10.0	10.0	EtOH	r.t.	98	3
  9	10.0	10.0	MeOH	r.t.	91	5
  10	10.0	10.0	H2O	r.t.	90	—
  11	10.0	10.0	DMF	r.t.	87	—
  12	10.0	10.0	Pyridine	r.t.	76	—
  13	10.0	10.0	Toluene	r.t.	2	—
  14	10.0	10.0	Et2O	r.t.	38	—
  15	10.0	10.0	1, 4-Dioxane	r.t.	41	—
  a Reagents and conditions: benzaldehyde (1.0 mmol), nitromethane (10.0 mmol), solvent (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

  Under the standard conditions, using Cu(OAc)₂•H₂O as catalyst, i-PrOH as solvent, ligands 1c~1f were further investigated as auxiliary catalysts for the Henry reaction of different aryl-aldehydes with nitromethane. The results were listed in Table 3. The reactions worked well and ge- nerated the Henry products in moderate to excellent results in terms of yield and enationselectivity. For aromatic aldehydes tested, the present system tolerated both electron-withdrawing and electron-donating substituents, and the substituent on the phenyl ring showed limited effect on the enantioselectivity (Table 3, Entries 2~14). Reaction of 2-naphthaldehyde produced the corresponding adducts with low yield and high enantioselectivity, which can be tentatively attributed to the large sterical hindrance of the aldehyde (Table 3, Entries 15~16).

  Table 3

  

  Table 3.  Henry reactions of aryl-aldehydes with nitromethane catalyzed by Cu(OAc)₂ with 1c~1f ^a

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  Entry	Ligand	Ar'	Product	Yield/%	ee/%
  1	1c	C6H5	3a	97	17
  2	1c	4-ClC6H4	3b	77	79
  3	1d	4-ClC6H4	3b	58	89
  4	1e	4-ClC6H4	3b	63	92
  5	1f	4-ClC6H4	3b	57	95
  6	1c	4-BrC6H4	3c	66	88
  7	1d	4-BrC6H4	3c	60	98
  8	1e	4-BrC6H4	3c	81	93
  9	1f	4-BrC6H4	3c	67	＞99
  10	1d	2-BrC6H4	3d	61	92
  11	1e	2-BrC6H4	3d	89	＞99
  12	1f	2-BrC6H4	3d	64	97
  13	1e	2-CH3OC6H4	3e	76	＞99
  14	1f	2-CH3OC6H4	3e	51	54
  15	1d	2-Naphthyl	3f	36	＞99
  16	1e	2-Naphthyl	3f	38	＞99
  a Reagents and conditions: aromatic aldehyde (1.0 mmol), nitromethane (10.0 mmol), i-PrOH (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

  Considering the coordination ability and steric effect of the substituent on imidazole C2, pyridinyl was the most favorable one for the formation of hydroxyl-pyridinyl- chelated copper complex, which might be catalytic active species for the reaction. We proposed a possible catalytic transition state for our system based on the generally accepted model proposed by Jrgensen^[23] and Kodama et al.^[64] (Figure 2). Due to Jahn-Teller distortion, the Cu(II) complex with an octahedral geometry has four strong coordination sites at the equatorial positions and two weak coordination sites at the apical positions. Addition of bidentate ligand 1c afforded the complex, in which the two neighboring strong coordination sites were occupied by OH and C2-pyridinyl group. Under the coordination influence of the complex, the multi-aryl substituted imidazole alcohol causes an obvious steric hindrance to leave space and provides two weak coordination sites at the apical positions of the metal complex. Both the aryl-aldehyde and nitromethane are efficiently activated by coordination to the equatorial and apical positions of the copper complex, respectively. The nitromethane approaches from the unoccupied upper side of the copper ion, forming a transition state. The rigid multi-aryl substituted imidazole and phen- ylpropyl of 1c occupy the major space around the transition state to leave only the above space, whereas the benzaldehyde molecule with less steric hindrance is coordinated to the metal atom via the less-crowded space to give (S)-enantiomer. The donor ability of C2-substitutent is essential for the asymmetric induction.

  Figure 2

  

  Figure 2.  Proposed transition state of the Henry reaction catalyzed by 1c/Cu(OAc)₂

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  3.   Conclusions

  A series of multi-aryl substituted imidazole amino alcohol derivatives 1a~1f containing appended chiral functionalities were synthesized by using L-phenylalaninol as chiral source. Application of ligands 1a~1f in asymmetric copper-catalyzed Henry reactions showed that C2- heteroaryl substituted ligands 1c~1f, in combination with Cu(OAc)₂•H₂O, were able to promote a highly enantioselective Henry reaction between nitromethane and aromatic aldehydes, providing β-hydroxynitro compounds in high yields and excellent enantioselectivities with S configuration. A possible catalytic transition state for the system was proposed and application of these convenient available chiral ligands to other enantioselective catalytic processes is in progress in our laboratory.

  4.   Experimental section

  4.1   General

  All experiments were performed in air. All reagents and solvents were analytical grade materials purchased from commercial sources and used as received unless otherwise stated. Reactions were monitored by TLC (Qingdao Haiyang Chemical Co. Ltd. Silica gel 60 F₂₅₄) and detected using an UV/Vis lamp (254 nm). Column chromatography was performed on Qingdao Haiyang Chemical Co. Ltd. Gel 60 (200~300 mesh).

  NMR spectra were recorded at 25 ℃ on a 400 MHz Bruker spectrometer. Chemical shifts were referenced to the internal solvent (DMSO-d₆, δ_H 2.50, δ_C 40.0). ESI-MS spectra were recorded on a Bruker Esquire 3000. Elemental analysis were obtained from a Thermo Flash 2000.

  4.2   General procedure for the preparation of chiral ligands 1a~1f

  To a solution of L-phenylalaninol (15.1 g, 0.1 mol) in MeOH (50 mL) in an ice-bath, molar equivalent of dibenzoyl, aryl-aldehyde and ammonium acetate were added. The mixture was kept stirring in the ice-bath until all the solids were dissolved before being heated to 60 ℃ for 5 h. The mixture was then cooled to room temperature and the solvent was removed by evaporation. The residue was washed with H₂O to obtain the crude product. Crystallization of the crude product in EtOH afforded colorless crystals of 1a~1f.

  (S)-3-Phenyl-2-(2, 4, 5-triphenyl-1H-imidazol-1-yl)pro- pan-1-ol (1a): Yield 87%. m.p. 230~231 ℃; －73.51 (c 0.0430, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.56~6.77 (m, 20H, ArH), 5.25 (t, J＝8.0 Hz, 1H, NCH), 3.70~3.64 (m, 1H, CH₂OH), 3.48~3.39 (m, 1H, CH₂OH), 2.79~2.73 (m, 1H, CH₂Ph), 2.65~2.61 (m, 1H, CH₂Ph); ¹³C NMR (100 MHz, DMSO-d₆) δ: 138.2, 135.3, 132.6, 130.5, 129.7, 129.3, 129.1, 129.0, 128.8, 128.7, 128.4, 126.9, 126.3, 62.8, 61.4, 37.4; IR (KBr) v: 3153, 3057, 3026, 2841, 1954, 1882, 1819, 1601, 1498, 1442, 1358, 1122, 1074, 1033, 962, 773, 698, 557 cm^－1; ESI-MS m/z: 431.1 [M+H]⁺. Anal. calcd for C₃₀H₂₆N₂O: C 83.69, H 6.09, N 6.51; found C 83.48, H 5.88, N 6.59.

  (S)-2-(4, 5-Diphenyl-2-(p-tolyl)-1H-imidazol-1-yl)-3- phenylpropan-1-ol (1b): Yield 89%. m.p. 199~200 ℃; －23.38 (c 0.0005, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.54~6.78 (m, 19H, ArH), 5.23 (t, J＝4.0 Hz, 1H, NCH), 3.69~3.41 (m, 2H, CH₂OH), 2.78~2.72 (m, 1H, CH₂Ph), 2.65~2.60 (m, 1H, CH₂Ph), 2.38 (s, 3H, PhCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 138.6, 138.2, 135.3, 132.6, 130.4, 129.6, 129.2, 129.0, 128.8. 128.4, 126.9, 126.3, 62.9, 61.6, 37.3, 21.4; IR (KBr) v: 3153, 3060, 3030, 2968, 2914, 2854, 1965, 1896, 1809, 1603, 1500, 1441, 1386, 1074, 1053, 964, 827, 781, 696, 523 cm^－1; ESI-MS m/z: 445.1 [M+H]⁺. Anal. calcd for C₃₁H₂₈N₂O: C 83.75, H 6.35, N; 6.30; found C 83.55, H 6.16, N; 6.43.

  (S)-2-(4, 5-Diphenyl-2-(pyridin-2-yl)-1H-imidazol-1-yl)-3-phenylpropan-1-ol (1c): Yield 90%. m.p. 144~145 ℃; －88.68 (c 0.0149, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.73~6.80 (m, 19H, ArH), 4.98 (t, J＝4.0 Hz, 1H, NCH), 4.41~3.70 (m, 2H, CH₂OH), 3.15~2.69 (m, 2H, CH₂Ph); ¹³C NMR (100 MHz, DMSO-d₆) δ: 151.6, 148.5, 145.6, 138.9, 137.5, 135.1, 132.3, 129.4, 129.2, 128.7, 128.5, 126.8, 126.6, 126.5, 125.2, 123.6, 63.0, 62.3, 37.3; IR (KBr) v: 3147, 3055, 2918, 2843, 1954, 1892, 1601, 1589, 1498, 1433, 1363, 1282, 1128, 1055, 995, 968, 912, 758, 696, 621, 559 cm^－1; ESI-MS m/z: 432.3 [M+H]⁺. Anal. calcd for C₂₉H₂₅N₃O: C 80.72, H 5.84, N 3.71; found C 80.58, H 5.66, N; 3.83.

  (S)-2-(2-(6-Methylpyridin-2-yl)-4, 5-diphenyl-1H-imidazol-1-yl)-3-phenylpropan-1-ol (1d): Yield 90%. m.p. 60~61 ℃; －52.36 (c 0.0023, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.86 (t, J＝6.8 Hz, 2H, ArH), 7.49~7.47 (m, 3H, ArH), 7.34~7.29 (m, 4H, ArH), 7.18~7.07 (m, 7H, ArH), 6.85~6.81 (m, 2H, ArH), 4.96 (t, J＝4.0 Hz, 1H, NCH), 4.06~4.00 (m, 2H, CH₂OH), 3.18 (d, J＝4.0 Hz, 2H, CH₂Ph), 2.61 (s, 3H, PhCH₃); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.8, 156.8, 150.9, 139.0, 137.7, 135.0, 132.2, 129.3, 129.1, 128.7, 128.4, 126.7, 126.5, 126.4, 122.8, 122.1, 62.9, 60.2, 24.2, 21.2; IR (KBr) v: 3059, 3026, 2952, 2922, 2852, 1950, 1890, 1807, 1736, 1574, 1454, 1350, 1028, 775, 696 cm^－1; ESI-MS m/z: 446.4 [M+H]⁺. Anal. calcd for C₃₀H₂₇N₃O: C 80.87, H 6.11, N 9.43; found C 80.59, H 6.01, N; 9.64.

  (S)-2-(4, 5-Diphenyl-2-(quinolin-2-yl)-1H-imidazol-1-yl)- 3-phenylpropan-1-ol (1e): Yield 70%. m.p. 128~129 ℃; －86.25 (c 0.0072, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 8.51 (s, 2H, ArH), 8.14~8.06 (m, 2H, ArH), 7.88~7.84 (m, 1H, ArH), 7.68 (t, J＝7.5 Hz, 1H, ArH), 7.50~7.49 (m, 3H, ArH), 7.34 (d, J＝7.2 Hz, 3H, ArH), 7.19~7.10 (m, 7H, ArH), 6.78 (bs, 2H, ArH), 4.99 (bs, 1H, NCH), 4.12~3.97 (m, 2H, CH₂OH), 3.17 (d, J＝4.0 Hz, 2H, CH₂Ph); ¹³C NMR (100 MHz, DMSO-d₆) δ: 151.1, 146.7, 139.0, 137.0, 134.9, 132.1, 130.6, 129.8, 129.4, 129.2, 129.0, 128.9, 128.7, 128.5, 128.4, 127.4, 127.3, 126.7, 126.5, 122.7, 63.0, 61.8, 37.1; IR (KBr) v: 3267, 3053, 3026, 2931, 2887, 2389, 2332, 1589, 1560, 1504, 1473, 1363, 1045, 964, 835, 775, 758, 698, 561 cm^－1; ESI-MS m/z: 482.4 [M+H]⁺. Anal. calcd for C₃₃H₂₇N₃O: C 82.30, H 5.65, N 8.73; found C 82.09, H 5.45, N; 8.70.

  (S)-2-(4, 5-Diphenyl-2-(thiophen-2-yl)-1H-imidazol-1-yl)-3-phenylpropan-1-ol (1f): Yield 90%. m.p. 189~190 ℃; －134.27 (c 0.0218, CH₂Cl₂); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.69~7.55 (m, 5H, ArH), 7.26 (d, J＝7.5 Hz, 2H, ArH), 7.17~7.07 (m, 9H, ArH), 6.83 (bs, 2H, ArH), 5.25 (bs, 1H, NCH), 3.70~3.52 (m, 2H, CH₂OH), 2.82~2.72 (m, 2H, CH₂Ph); ¹³C NMR (100 MHz, DMSO-d₆) δ: 143.3, 138.2, 134.9, 132.5, 129.8, 129.3, 129.0, 128.9, 128.5, 127.6, 127.0, 126.6, 126.5, 63.0, 60.3, 37.1; IR (KBr) v: 3183, 3057, 2922, 2852, 2362, 2341, 2025, 1961, 1815, 1784, 1601, 1498, 1441, 1414, 1360, 1244, 1057, 1049, 949, 849, 788, 702, 594, 555, 532, 499 cm^－1; ESI-MS m/z: 437.3 [M+H]⁺. Anal. calcd for C₂₈H₂₄N₂OS: C 77.03, H 5.54, N; 6.42; found C 76.80, H 5.25, N 6.70.

  4.3   General procedure for the catalytic Henry reaction

  One of the ligands 1a~1f (0.2 mmol) and Cu(OAc)₂• H₂O (40.0 mg, 0.2 mmol) were added to i-PrOH (2.0 mL) and the mixture was stirred for 30 min at room temperature. Then aryl-aldehyde (1.0 mmol) and CH₃NO₂ (0.54 mL, 10.0 mmol) were added and the mixture was stirred for the time indicated in the Tables. The solvents were removed under reduced pressure, and the crude product was purified by column chromatography [silica, V(AcOEt)/ V(hexane)＝1/4].

  Stereochemical assignments. The absolute configurations of compound 3e were assigned as S by comparison of its optical rotations with literature values.^[30] The absolute configurations of the remaining examples were assigned by analogy.

  2-Nitro-1-phenylethan-1-ol (3a): ¹H NMR (400 MHz, DMSO-d₆) δ: 7.46~7.30 (m, 5H, ArH), 6.15 (s, 1H, CHOH), 5.29 (dd, J＝3.3, 10.0 Hz, 1H, CHOH), 4.85 (dd, J＝3.4, 12.5 Hz, 1H, CH₂NO₂), 4.60~4.55 (m, 1H, CH₂NO₂). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopro-panol)＝85:15, 0.8 mL/min, 215 nm], major enantiomer t_r＝13.96 min, minor enantiomer t_r＝17.13 min.

  1-(4-Chlorophenyl)-2-nitroethan-1-ol (3b): ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49~7.41 (m, 4H, ArH), 6.23 (d, J＝4.8 Hz, 1H, CHOH), 5.33~5.29 (m, 1H, CHOH), 4.84 (dd, J＝3.1, 12.5 Hz, 1H, CH₂NO₂), 4.61~4.56 (m, 1H, CH₂NO₂). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopropanol)＝85:15, 0.8 mL/min, 254 nm], major enantiomer t_r＝11.60 min, minor enantiomer t_r＝13.07 min.

  1-(4-Bromophenyl)-2-nitroethan-1-ol (3c): ¹H NMR (400 MHz, DMSO-d₆) δ: 7.57 (d, J＝8.4 Hz, 2H, ArH), 7.40 (d, J＝8.4 Hz, 2H, ArH), 6.20 (dd, J＝0.6, 5.0 Hz, 1H, CHOH), 5.29~5.24 (m, 1H, CHOH), 4.88~4.83 (m, 1H, CH₂NO₂), 4.59~4.54 (m, 1H, CH₂NO₂). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopropanol)＝85:15, 0.8 mL/min, 254 nm], major enantiomer t_r＝11.87 min, minor enantiomer t_r＝13.60 min. +12.17 (c 0.09, CH₂Cl₂), (99% ee, (S)-isomer).

  1-(2-Bromophenyl)-2-nitroethan-1-ol (3d): ¹H NMR (400 MHz, DMSO-d₆) δ: 7.68~7.62 (m, 2H, ArH), 7.48~7.44 (m, 1H, ArH), 7.31~7.27 (m, 1H, ArH), 6.39 (d, J＝4.4 Hz, 1H, CHOH), 5.60~5.55 (m, 1H, CHOH), 4.79 (dd, J＝2.2, 12.64 Hz, 1H, CH₂NO₂), 4.50~4.45 (m, 1H, CH₂NO₂). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopro-panol)＝85:15, 0.8 mL/min, 254 nm], major enantiomer t_r＝10.78 min, minor enantiomer t_r＝11.77 min. +6.82 (c 0.02, CH₂Cl₂), (99% ee, (S)-isomer).

  1-(2-Methoxyphenyl)-2-nitroethan-1-ol (3e): ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49~7.47 (m, 1H, ArH), 7.33~7.29 (m, 1H, ArH), 7.03~6.98 (m, 2H, ArH), 5.99 (d, J＝4.6 Hz, 1H, CHOH), 5.56~5.52 (m, 1H, CHOH), 4.73 (dd, J＝2.1, 12.2 Hz, 1H, CH₂NO₂), 4.40~4.34 (m, 1H, CH₂NO₂), 3.83 (s, 3H, CH₃). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopropanol)＝85:15, 0.8 mL/min, 254 nm], major enantiomer t_r＝13.04 min, minor enantiomer t_r＝15.00 min.

  1-(Naphthalen-2-yl)-2-nitroethan-1-ol (3f): ¹H NMR (400 MHz, DMSO-d₆) δ: 8.04~7.91 (m, 4H, ArH), 7.67~7.50 (m, 3H, ArH), 6.27 (d, J＝4.8 Hz, 1H, CHOH), 5.47~5.42 (m, 1H, CHOH), 4.97 (dd, J＝3.3, 12.5 Hz, 1H, CH₂NO₂), 4.69~4.64 (m, 1H, CH₂NO₂). Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column [V(hexane):V(isopropanol)＝85:15, 0.8 mL/min, 215 nm], major enantiomer t_r＝20.97 min, minor enantiomer t_r＝28.37 min.

  Supporting Information  ESI-MS, ¹H NMR and ¹³C NMR spectra of ligands 1a~1f. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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• 

  Scheme 1  Synthesis of multi-aryl substituted imidazole amino alcohol derivatives 1a~1f

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  Figure 1  ORTEP drawing of the molecular structures of ligands 1f at 30% probability displacement ellipsoids. Aromatic, methylene and methyne hydrogen atoms are omitted for clarity

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  Figure 2  Proposed transition state of the Henry reaction catalyzed by 1c/Cu(OAc)₂

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  Table 1.  Screening of ligands (1a~1f) and copper source

  Entrya	Ligand	Copper salts	Yield/%	ee/%
  1	—	Cu(OAc)2•H2O	15	3
  2	1a	Cu(OAc)2•H2O	48	3
  3	1b	Cu(OAc)2•H2O	62	2
  4	1c	Cu(OAc)2•H2O	97	17
  5	1d	Cu(OAc)2•H2O	77	13
  6	1e	Cu(OAc)2•H2O	68	10
  7	1f	Cu(OAc)2•H2O	73	10
  8	1c	CuBr2	56	5
  9	1c	CuBr	10	8
  10	1c	CuCl2	12	11
  11	1c	CuI2	38	6
  a Reagents and conditions: benzaldehyde (1.0 mmol), nitromethane (10.0 mmol), i-PrOH (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

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  Table 2.  Effects of catalyst loading, temperature and solvent on the reaction^a

  Entry	1c/ mol%	Cu(OAc)2•H2O/ mol%	Solvent	Temp.	Yield/%	eeb/%
  1	—	—	i-PrOH	r.t.	13	—
  2	10.0	10.0	i-PrOH	r.t.	97	17
  3	20.0	20.0	i-PrOH	r.t.	98	17
  4	10.0	—	i-PrOH	r.t.	22	5
  5	—	10.0	i-PrOH	r.t.	15	3
  6	10.0	10.0	i-PrOH	0	71	18
  7	10.0	10.0	i-PrOH	50	98	8
  8	10.0	10.0	EtOH	r.t.	98	3
  9	10.0	10.0	MeOH	r.t.	91	5
  10	10.0	10.0	H2O	r.t.	90	—
  11	10.0	10.0	DMF	r.t.	87	—
  12	10.0	10.0	Pyridine	r.t.	76	—
  13	10.0	10.0	Toluene	r.t.	2	—
  14	10.0	10.0	Et2O	r.t.	38	—
  15	10.0	10.0	1, 4-Dioxane	r.t.	41	—
  a Reagents and conditions: benzaldehyde (1.0 mmol), nitromethane (10.0 mmol), solvent (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

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  Table 3.  Henry reactions of aryl-aldehydes with nitromethane catalyzed by Cu(OAc)₂ with 1c~1f ^a

  Entry	Ligand	Ar'	Product	Yield/%	ee/%
  1	1c	C6H5	3a	97	17
  2	1c	4-ClC6H4	3b	77	79
  3	1d	4-ClC6H4	3b	58	89
  4	1e	4-ClC6H4	3b	63	92
  5	1f	4-ClC6H4	3b	57	95
  6	1c	4-BrC6H4	3c	66	88
  7	1d	4-BrC6H4	3c	60	98
  8	1e	4-BrC6H4	3c	81	93
  9	1f	4-BrC6H4	3c	67	＞99
  10	1d	2-BrC6H4	3d	61	92
  11	1e	2-BrC6H4	3d	89	＞99
  12	1f	2-BrC6H4	3d	64	97
  13	1e	2-CH3OC6H4	3e	76	＞99
  14	1f	2-CH3OC6H4	3e	51	54
  15	1d	2-Naphthyl	3f	36	＞99
  16	1e	2-Naphthyl	3f	38	＞99
  a Reagents and conditions: aromatic aldehyde (1.0 mmol), nitromethane (10.0 mmol), i-PrOH (2 mL), a week. b Enantiomeric excesses were determined by HPLC using Chiralcel OD-H.

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•