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Cite this: DOI: 10.1039/c5cc02302e Received 19th March 2015, Accepted 2nd April 2015 DOI: 10.1039/c5cc02302e
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Solvent-dependent strong asymmetric amplification in the catalytic enantioselective Henry reaction using the trans-N,N 0 -bis-biphenyl-4-ylmethylcyclohexane-1,2-diamine-CuCl2 complex† Koichi Tanaka,*a Tomoharu Iwashita,a Erika Yoshida,a Tomomi Ishikawa,a Shinya Otuka,a Zofia Urbanczyk-Lipkowskab and Hiroki Takahashic
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A strong asymmetric amplification was observed in the enantioselective Henry reaction catalyzed by the (R,R)-trans-N,N 0 -bis-biphenyl-4ylmethyl-cyclohexane-1,2-diamineCuCl2 complex in AcOEt, while no amplification occurred in MeOH.
The asymmetric Henry (nitroaldol) reaction provides easy access to chiral b-nitroalcohols, which can be further transformed into valuable chiral building blocks such as 1,2-aminoalcohols,1 through both organocatalytic and metal-catalysed protocols.2 In this area, chiral copper complexes such as Cu(II)-bisoxazoline,3 Cu(II)bisimidazoline,4 camphor-derived Cu(II)-iminopyridine ligands,5 Cu(II)-sparteine,6 Cu(II)–C2-symmetric chiral secondary diamines,7 Cu(II) chiral trianglamine,8 and Cu(II) chiral pyrrole macrocyclic
a
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan. E-mail: [email protected]; Fax: +81-06-6339-4026; Tel: +81-06-6368-0861 b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01224 Warsaw, Poland c Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan † Electronic supplementary information (ESI) available: Experimental procedures for the catalytic Henry reaction. CCDC 1038527 (4), 1042149 (3) and 1042150 (5). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc02302e
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ligands9 have attracted much attention. The enantiomeric purity of a product is greatly enhanced in relation to that of the chiral catalyst10 because of asymmetric amplification, which is a positive nonlinear effect. This enables synthesis of a high-enantiomeric excess (ee) chiral product without a high-ee chiral catalyst. Although this process is widely accepted, there is only one report on asymmetric amplification in a catalytic Henry reaction.11 In the present study, an unprecedented strong solvent-dependent asymmetric amplification was observed in an enantioselective Henry reaction catalyzed by a CuC2 complex of (R,R)-trans-N,N0 -bisbiphenyl-4-yl methyl cyclohexane-1,2-diamine (1a) in AcOEt. (R,R)-1a was prepared from (R,R)-trans-1,2-diaminocyclohexane using a previously reported method.12 Asymmetric Henry reactions were performed as follows: (R,R)-1a (0.05 mmol) and CuCl2 (0.05 mmol) were treated with MeOH (1.0 mL). The resulting blue solution was stirred for 30 s at 60 1C and then for 1 h at 25 1C. Subsequently, a solution of benzaldehyde (0.5 mmol) and CH3NO2 (5.0 mmol) in MeOH (0.5 mL) was added, followed by triethylamine (0.05 mmol). The reaction mixture was stirred at 0 1C. After 24 h, the cold reaction mixture was placed into a silica-gel plug (n-hexane/ AcOEt 1 : 1, v/v) and the desired b-nitroalcohol (S)-2a was obtained with 77% ee in 73% yield (Table 1, entry 1). The role of the solvents in the asymmetric reaction was examined and the results are listed in Table 1. AcOEt gave the best results (87% yield with 91% ee; Table 1, entry 4). Next, we examined the scope of this catalytic system in the reaction of various aldehydes. Different aldehydes
Table 1 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of the (R,R)-1aCuCl2 complexa
Entry
Solvent
Yield (%)
ee (%)
1 2 3 4
MeOH CH3CN THF AcOEt
73 72 52 87
77 80 92 91
a
Reaction conditions: benzaldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), solvent (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD column.
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Table 2 Catalytic asymmetric Henry reaction of aldehydes with nitromethane in the presence of the (R,R)-1aCuCl2 complexa
Entry
R
Yield (%)
ee (%)
1 2 3 4 5 6
Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 2-ClC6H4 cyclo-C6H11
87 67 45 79 87 69
91 86 72 82 80 92
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a
Reaction conditions: aldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD–H column.
were converted into nitroaldol adducts with good to excellent enantioselectivities (Table 2, entries 2–6). When the reaction of benzaldehyde and nitroethane was carried out under similar conditions, a 48 : 52 mixture of anti-(61% ee) and syn-2-nitro1-phenylpropan-1-ol (79% ee) was obtained. The effect of metal salts on the enantioselectivity was also investigated. When Cu(OAc)2 was used instead of CuCl2, both the enantioselectivity and reactivity decreased (Table 3, entry 2). Then, when the reaction was performed in the presence of either ZnCl2 or Zn(OAc)2, almost no reaction occurred (Table 3, entries 3 and 4). An unprecedented, strong, positive asymmetric amplification of the product (S)-2a was observed during these experiments using the low-ee chiral ligand (R,R)-1 in combination with CuCl2 in AcOEt. For example, (R,R)-1a with 80% ee catalyst produced (S)-2a with 91% ee (Table S1, ESI,† entry 2). The ee of the product (S)-2a did not greatly decrease until the optical purity of the catalyst dropped below 10% ee (Fig. 1). Similarly, the reaction mediated by ligand (R,R)-1a with 5% ee produced (S)-2a with 64% ee. Hence, the (R,R)-1a-CuCl2 catalyzed formation of b-nitroalcohol (S)-2a exhibits a strong positive nonlinear effect. In addition, a positive nonlinear effect was observed in CH3CN (Fig. S1, ESI†) and partially in THF (Fig. S2, ESI†). Interestingly, the asymmetric reaction in MeOH suggested an almost linear relationship between the ee of ligand (R,R)-1a and that of the product (S)-2a (Fig. 2). The asymmetric reaction in the presence of the (R,R)-1a-Cu(OAc)2 complex in AcOEt showed a linear relationship as described in Fig. S3 in the ESI†. The fact that (R,R)-1a-CuCl2 easily dissolves in AcOEt, whereas rac-1a-CuCl2 does not, might account for the nonlinear effect. The large solubility difference between (R,R)- and rac-1a-CuCl2 selectively increases the purity of the major enantiomer in the
Table 3 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of the (R,R)-1aMX2 complexa
Entry
MX2
Yield (%)
ee (%)
1 2 3 4
CuCl2 Cu(OAc)2 ZnCl2 Zn(OAc)2
87 80 Trace Trace
91 88 0 0
a
Reaction conditions: benzaldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), MX2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD column.
Chem. Commun.
Fig. 1 Relationship between the enantiomeric excess (ee) of ligand (R,R)-1a and that of product (S)-2a in the catalytic reaction in AcOEt.
Fig. 2 Relationship between the enantiomeric excess (ee) of ligand (R,R)-1a and that of product (S)-2a in the catalytic reaction in MeOH.
AcOEt solution and creates a positive nonlinear effect. By contrast, a large solubility difference was not observed between (R,R)- and rac-1a-CuCl2 in MeOH. In this case, chiral amplification originated from the thermodynamically controlled crystallization of the rac-1aCuCl2 complex, whereas the enantiomeric surplus remained in the solution and was available for asymmetric catalysis (Scheme 1). A similar asymmetric amplification has been reported in a proline catalyzed aldol reaction, where preferential crystallization of rac-proline was observed.13 We also examined the effect of asymmetric amplification of substituents on the aromatic ring of the chiral ligands (R,R)1a–1d. As shown in Table 4, a strong symmetric amplification was observed when the ligands 1a–1c with electron donating groups were used in the reactions (entries 1–3), while no amplification occurred in the reactions using 1d and 1e with electron withdrawing groups (entries 4 and 5). However, it is not obvious why ligand 1e does not show this effect, but ligand 1b does. To describe the strong nonlinear effect in the (R,R)-1a-CuCl2 catalyzed asymmetric Henry reactions, X-ray crystal structures of [(R,R)-1a-CuCl2]22(AcOEt) 3, (R,R)-1a-CuCl22(THF) 4, and rac1a-CuCl2 5 were determined. These complexes were obtained from the reaction of (R,R)-1a with CuCl2, using AcOEt, THF, and MeOH as the solvents.
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Fig. 3 X-ray structure of an asymmetric unit of [(R,R)-1aCuCl2]22(AcOEt) 3 showing a bidentate structure and a distorted square-pyramidal copper coordination geometry. Ligand EtOAc hydrogen bonding geometry: N1 O1 [x, y + 1/2, z] = 3.019(2), N1–H1N = 0.84(2), H1 O1 = 2.18 (2) Å, angle N1–H1 O1 = 175(2)1; N4 O3 [x, y, z + 1] = 2.947(2), N4–H4N = 0.86(2), H4 O3 = 2.16(2) Å, angle N4–H4 O3 = 152(2)1. Scheme 1
Table 4 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of (R,R)-1a–eCuCl2 complexesa
Entry
Ligand
Yield (%)
ee (%)
Amplificationb
1 2 3 4 5
(R,R)-1a (R,R)-1b (R,R)-1c (R,R)-1d (R,R)-1e
87 37 60 63 63
91 93 89 90 92
Yes Yes Yes No No
a
Reaction conditions: aldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1 (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD-H column. b See Fig. S4–S7.
The X-ray structures of 3, 4, and 5 provide insights into the conformational preferences of the chiral ligand [(R,R)-1a] and its coordination versatility when complexed with CuCl2. Both monoand bidentate copper coordination geometries were observed. The Cu atom in 3 was pentacoordinated and formed a bidentate coordination sphere with the apical positions occupied by Cl atoms (Fig. 3).‡ The Cu atom in the chiral complex 4 had a flattened tetrahedral coordination (Fig. 4),§ whereas nearly square-planar coordination geometry was observed in the achiral complex 5 (Fig. 5).¶ Moreover, irrespective of the Cu coordination mode the free H-atoms of the ligand amine groups served as proton donors in hydrogen bonds with solvent molecules (e.g. AcOEt or THF) in 3 and 4. In 5, the above-mentioned protons formed hydrogen bonded polymeric chains with chloride anions as shown in Fig. 6. The inability to form hydrogen bonds with solvent molecules contributes to the differences in solubility observed between chiral complexes 3 and 4 and racemic complex 5. The cyclohexane ring in each of the three complexes adopted a chair conformation. The diphenymethylamino arms were twisted outwards from the coordination sphere, allowing association with two solvent molecules or propagation of the hydrogen bonded polymeric chain. The generally accepted mechanism2c of the Henry reaction assumes
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Fig. 4 X-ray structure of [(R,R)-1aCuCl2]22(THF) 4 showing a flattened tetrahedral copper coordination geometry. Ligand THF hydrogen bonding geometry: N1 O1 = 2.959(2) [2 x, y, 2 z], N1–H = 0.83(2), H O1 = 2.13(2), Å, angle 170(2)1.
Fig. 5 X-ray structure of rac-1aCuCl2 5 with a square-planar copper coordination geometry.
simultaneous coordination of the enol form of nitromethane and benzylaldehyde to a less-hindered site because of coordination of the ligand Cu atom. Although it is not confirmed what model of Cu coordination is present in solution, it is obvious that in the case of the (R,R)-1a-CuCl2 catalyst, the coordination process is competitive to the formation of ligand–aprotic solvent hydrogen bonding. However, hydrogen bonding with the nucleophile present in the reaction mixture will be preferred.
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¶ Crystal data for the complex rac-1a-CuCl2 5: C32H34Cl2CuN2, FW = 581.05, monoclinic, space group C2/c, Z = 4, a = 25.8780(6) Å, b = 10.4574(2) Å, c = 10.7037(3) Å, b = 102.636(2)1, V = 2826.44(12) Å3, T = 150(2) K, m(CuKa) = 3.000 mm1, Dcalc = 1.365 g mm3, 8188 reflections were measured (4.581 o Y o 66.591), 2472 unique reflections (Rint = 0.0341) were corrected for numerical absorption (Tmin = 0.4948 and Tmax = 0.8744). The final R1 was 0.0431 for 2199 reflections with I 4 2s(I) and wR2 was 0.1131 (all data), GOF = 1.032. Fig. 6 Hydrogen bonded polymeric chain observed in rac-1aCuCl2 5: N1 Cl1 [x, y, z 1/2] = 3.113(2), N1–H1 = 0.87, H1 Cl1 = 2.32(2) Å, angle N1–H1 Cl1 = 170(2)1.
In conclusion, a chiral Cu(II) complex of (R,R)-1a was successfully used in the asymmetric Henry reaction. The use of this complex induced a positive nonlinear effect because of the inherent low solubility of the racemate in aprotic organic solvents such as AcOEt. The racemic 1a-CuCl2 monomer complex formed a thermodynamically more stable crystal lattice and was much less soluble in AcOEt than the enantiopure complex. This rare solid–liquid phase behavior increases the enantiomeric purity of the (R,R)-1a-CuCl2 dimer complex in the solution, and creates a large positive nonlinear effect that cannot thermodynamically control crystallization. This allows the major enantiomer in the solution to remain available for asymmetric catalysis. Studies that aim to clarify the mechanistic aspects and extension of this catalyst to other asymmetric reactions are currently underway in our laboratory. This study was supported by a Kansai University Special Research Fund, 2014.
Notes and references ‡ Crystal data for the complex [(R,R)-1a-CuCl2]22(AcOEt) 3: C72H84Cl4Cu2N4 O4, M = 1338.31, monoclinic, P21, Z = 2, a = 13.8568(3) Å, b = 15.8847(4) Å, c = 15.2073(4) Å, b = 96.0460(10)1, V = 3328.7(1) Å, T = 150(2) K, m(CuKa) = 2.664 mm1, Dcalc = 1.335 g mm3; 35 306 reflections were measured (4.041 o Y o 67.551), 9740 unique reflections (Rint = 0.0332) were corrected for experimental absorption (Tmin = 0.2045 and Tmax = 0.4627). The final R1 was 0.0270 for 9703 reflections with I 4 2s(I) and wR2 was 0.0697 (all data), GOF = 1.053. Absolute structure (Flack) parameter = 0.059(9). § Crystal data for the complex [(R,R)-1a-CuCl2]22(THF) 4: C40H50Cl2CuN2O2, FW = 725.26, monoclinic, space group C2, a = 13.608(3) Å, b = 10.347(2) Å, c = 14.528(4) Å, b = 117.341(3)1, V = 1817.1(7) Å3, T = 100(2) K, Z = 2, m(MoKa) = 0.785 mm1, 7381 reflections were measured (3.161 o Y o 27.491), 4090 independent reflections (Rint = 0.020) were corrected for experimental absorption (Tmin = 0.8401 and Tmax = 0.9048). The final R1 was 0.0224 for 3676 reflections with I 4 2s(I) and wR2 value was 0.0374 (all data), GOF = 0.866, Flack parameter = 0.017(6).
Chem. Commun.
1 (a) H. Sasai, T. Shibasaki, S. Arai, T. Arai and M. Shibasaki, J. Am. Chem. Soc., 1992, 114, 4418; (b) F. A. Luzzio, Tetrahedron, 2001, 57, 915; (c) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2008, 47, 3230; (d) R. Dodda, J. J. Goldman, T. Mandal, C.-G. Zhao, G. A. Broker and E. R. T. Tiekink, Adv. Synth. Catal., 2008, 350, 537. 2 For recent review, see: (a) J. Boruwa, N. Gogoi, P. P. Saikia and N. C. Barua, Tetrahedron: Asymmetry, 2006, 17, 3315; (b) C. Palomo, M. Oiarbide and ´ndez-Olmos A. Laso, Eur. J. Org. Chem., 2007, 2561; (c) G. Blay, V. Herna and J. R. Pedro, Synlett, 2011, 1195; (d) S. E. Milner, T. S. Moody and A. R. Maguire, Eur. J. Org. Chem., 2012, 3059; (e) C. Christensen, K. Juhl and K. A. Jørgensen, Chem. Commun., 2001, 2222. 3 D. A. Evans, D. Seidel, M. Rueping, H. W. Lam, J. T. Shaw and C. W. Downey, J. Am. Chem. Soc., 2003, 125, 12692. 4 K. Ma and J. You, Chem. – Eur. J., 2007, 13, 1863. 5 G. Blay, E. Climent, I. Fernandez, V. H. Olmos and J. R. Pedro, Tetrahedron: Asymmetry, 2007, 18, 1603. 6 H. Maheswaran, K. L. Prasanth, G. G. Krishna, K. Ravikumar, B. Sridhar and M. L. Kantam, Chem. Commun., 2006, 4066. 7 (a) T. Arai, M. Watanabe and A. Yanagisawa, Org. Lett., 2007, 9, 3595; (b) R. Kowalczyk, Ł. Sidorowicz and J. Skarzewski, Tetrahedron: Asymmetry, 2008, 19, 2310; (c) Q. T. Nguyen and J. H. Jeong, Polyhedron, 2008, 27, 3227; (d) R. Kowalczyk and J. Skarzewski, Tetrahedron: Asymmetry, 2009, 20, 2467. 8 (a) K. Tanaka and S. Hachiken, Tetrahedron Lett., 2008, 49, 2533; (b) D. Savoia, A. Gualandia and H. Stoeckli-Evans, Org. Biomol. Chem., 2010, 8, 3992. 9 A. Gualandi, L. Cerisoli, H. Stoeckli-Evans and D. Savoia, J. Org. Chem., 2011, 76, 3399. ˜ ach, S. Zhao, C. Agami and 10 (a) C. Puchot, O. Samuel, E. Dun H. B. Kagan, J. Am. Chem. Soc., 1986, 108, 2353; (b) D. Guillaneux, S.-H. Zhao, O. Samue, D. Rainford and H. B. Kagan, J. Am. Chem. Soc., 1994, 116, 9430; (c) K. Soai and S. Niwa, Chem. Rev., 1992, 92, 833; (d) L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757; (e) K. Soai, I. Sato and T. Kawasaki, in The Chemistry of Organozinc Compounds, ed. Z. Rappoprt and I. Marek, John Wiley & Sons, Chichester, UK, 2006, ch. 12, p. 555; ( f ) T. Satyanarayana, S. Abraham and H. B. Kagan, Angew. Chem., Int. Ed., 2009, 48, 456. 11 C. Palomo, M. Oiarbide and A. Laso, Angew. Chem., Int. Ed., 2005, 44, 3881. 12 V. G. Albano, M. Bandini, M. Melucci, M. Monari, F. Piccinelli, S. Tommasi and A. U. Ronchi, Adv. Synth. Catal., 2005, 347, 1507. 13 (a) Y. Hayashi, M. Matsuzawa, J. Yamaguchi, S. Yonehara, Y. Matsumoto, M. Shoji, D. Hashizume and H. Koshino, Angew. Chem., Int. Ed., 2006, 45, 4593; (b) M. Klussmann, H. Iwamura, S. P. Mathew, D. H. Wells, U. Pandya, A. Armstrong and D. G. Blackmond, Nature, 2006, 441, 621.
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Cite this: DOI: 10.1039/c5cc02302e Received 19th March 2015, Accepted 2nd April 2015 DOI: 10.1039/c5cc02302e
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Solvent-dependent strong asymmetric amplification in the catalytic enantioselective Henry reaction using the trans-N,N 0 -bis-biphenyl-4-ylmethylcyclohexane-1,2-diamine-CuCl2 complex† Koichi Tanaka,*a Tomoharu Iwashita,a Erika Yoshida,a Tomomi Ishikawa,a Shinya Otuka,a Zofia Urbanczyk-Lipkowskab and Hiroki Takahashic
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A strong asymmetric amplification was observed in the enantioselective Henry reaction catalyzed by the (R,R)-trans-N,N 0 -bis-biphenyl-4ylmethyl-cyclohexane-1,2-diamineCuCl2 complex in AcOEt, while no amplification occurred in MeOH.
The asymmetric Henry (nitroaldol) reaction provides easy access to chiral b-nitroalcohols, which can be further transformed into valuable chiral building blocks such as 1,2-aminoalcohols,1 through both organocatalytic and metal-catalysed protocols.2 In this area, chiral copper complexes such as Cu(II)-bisoxazoline,3 Cu(II)bisimidazoline,4 camphor-derived Cu(II)-iminopyridine ligands,5 Cu(II)-sparteine,6 Cu(II)–C2-symmetric chiral secondary diamines,7 Cu(II) chiral trianglamine,8 and Cu(II) chiral pyrrole macrocyclic
a
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan. E-mail: [email protected]; Fax: +81-06-6339-4026; Tel: +81-06-6368-0861 b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01224 Warsaw, Poland c Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan † Electronic supplementary information (ESI) available: Experimental procedures for the catalytic Henry reaction. CCDC 1038527 (4), 1042149 (3) and 1042150 (5). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc02302e
This journal is © The Royal Society of Chemistry 2015
ligands9 have attracted much attention. The enantiomeric purity of a product is greatly enhanced in relation to that of the chiral catalyst10 because of asymmetric amplification, which is a positive nonlinear effect. This enables synthesis of a high-enantiomeric excess (ee) chiral product without a high-ee chiral catalyst. Although this process is widely accepted, there is only one report on asymmetric amplification in a catalytic Henry reaction.11 In the present study, an unprecedented strong solvent-dependent asymmetric amplification was observed in an enantioselective Henry reaction catalyzed by a CuC2 complex of (R,R)-trans-N,N0 -bisbiphenyl-4-yl methyl cyclohexane-1,2-diamine (1a) in AcOEt. (R,R)-1a was prepared from (R,R)-trans-1,2-diaminocyclohexane using a previously reported method.12 Asymmetric Henry reactions were performed as follows: (R,R)-1a (0.05 mmol) and CuCl2 (0.05 mmol) were treated with MeOH (1.0 mL). The resulting blue solution was stirred for 30 s at 60 1C and then for 1 h at 25 1C. Subsequently, a solution of benzaldehyde (0.5 mmol) and CH3NO2 (5.0 mmol) in MeOH (0.5 mL) was added, followed by triethylamine (0.05 mmol). The reaction mixture was stirred at 0 1C. After 24 h, the cold reaction mixture was placed into a silica-gel plug (n-hexane/ AcOEt 1 : 1, v/v) and the desired b-nitroalcohol (S)-2a was obtained with 77% ee in 73% yield (Table 1, entry 1). The role of the solvents in the asymmetric reaction was examined and the results are listed in Table 1. AcOEt gave the best results (87% yield with 91% ee; Table 1, entry 4). Next, we examined the scope of this catalytic system in the reaction of various aldehydes. Different aldehydes
Table 1 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of the (R,R)-1aCuCl2 complexa
Entry
Solvent
Yield (%)
ee (%)
1 2 3 4
MeOH CH3CN THF AcOEt
73 72 52 87
77 80 92 91
a
Reaction conditions: benzaldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), solvent (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD column.
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Table 2 Catalytic asymmetric Henry reaction of aldehydes with nitromethane in the presence of the (R,R)-1aCuCl2 complexa
Entry
R
Yield (%)
ee (%)
1 2 3 4 5 6
Ph 4-MeC6H4 4-MeOC6H4 4-ClC6H4 2-ClC6H4 cyclo-C6H11
87 67 45 79 87 69
91 86 72 82 80 92
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a
Reaction conditions: aldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD–H column.
were converted into nitroaldol adducts with good to excellent enantioselectivities (Table 2, entries 2–6). When the reaction of benzaldehyde and nitroethane was carried out under similar conditions, a 48 : 52 mixture of anti-(61% ee) and syn-2-nitro1-phenylpropan-1-ol (79% ee) was obtained. The effect of metal salts on the enantioselectivity was also investigated. When Cu(OAc)2 was used instead of CuCl2, both the enantioselectivity and reactivity decreased (Table 3, entry 2). Then, when the reaction was performed in the presence of either ZnCl2 or Zn(OAc)2, almost no reaction occurred (Table 3, entries 3 and 4). An unprecedented, strong, positive asymmetric amplification of the product (S)-2a was observed during these experiments using the low-ee chiral ligand (R,R)-1 in combination with CuCl2 in AcOEt. For example, (R,R)-1a with 80% ee catalyst produced (S)-2a with 91% ee (Table S1, ESI,† entry 2). The ee of the product (S)-2a did not greatly decrease until the optical purity of the catalyst dropped below 10% ee (Fig. 1). Similarly, the reaction mediated by ligand (R,R)-1a with 5% ee produced (S)-2a with 64% ee. Hence, the (R,R)-1a-CuCl2 catalyzed formation of b-nitroalcohol (S)-2a exhibits a strong positive nonlinear effect. In addition, a positive nonlinear effect was observed in CH3CN (Fig. S1, ESI†) and partially in THF (Fig. S2, ESI†). Interestingly, the asymmetric reaction in MeOH suggested an almost linear relationship between the ee of ligand (R,R)-1a and that of the product (S)-2a (Fig. 2). The asymmetric reaction in the presence of the (R,R)-1a-Cu(OAc)2 complex in AcOEt showed a linear relationship as described in Fig. S3 in the ESI†. The fact that (R,R)-1a-CuCl2 easily dissolves in AcOEt, whereas rac-1a-CuCl2 does not, might account for the nonlinear effect. The large solubility difference between (R,R)- and rac-1a-CuCl2 selectively increases the purity of the major enantiomer in the
Table 3 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of the (R,R)-1aMX2 complexa
Entry
MX2
Yield (%)
ee (%)
1 2 3 4
CuCl2 Cu(OAc)2 ZnCl2 Zn(OAc)2
87 80 Trace Trace
91 88 0 0
a
Reaction conditions: benzaldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1a (0.05 mmol), MX2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD column.
Chem. Commun.
Fig. 1 Relationship between the enantiomeric excess (ee) of ligand (R,R)-1a and that of product (S)-2a in the catalytic reaction in AcOEt.
Fig. 2 Relationship between the enantiomeric excess (ee) of ligand (R,R)-1a and that of product (S)-2a in the catalytic reaction in MeOH.
AcOEt solution and creates a positive nonlinear effect. By contrast, a large solubility difference was not observed between (R,R)- and rac-1a-CuCl2 in MeOH. In this case, chiral amplification originated from the thermodynamically controlled crystallization of the rac-1aCuCl2 complex, whereas the enantiomeric surplus remained in the solution and was available for asymmetric catalysis (Scheme 1). A similar asymmetric amplification has been reported in a proline catalyzed aldol reaction, where preferential crystallization of rac-proline was observed.13 We also examined the effect of asymmetric amplification of substituents on the aromatic ring of the chiral ligands (R,R)1a–1d. As shown in Table 4, a strong symmetric amplification was observed when the ligands 1a–1c with electron donating groups were used in the reactions (entries 1–3), while no amplification occurred in the reactions using 1d and 1e with electron withdrawing groups (entries 4 and 5). However, it is not obvious why ligand 1e does not show this effect, but ligand 1b does. To describe the strong nonlinear effect in the (R,R)-1a-CuCl2 catalyzed asymmetric Henry reactions, X-ray crystal structures of [(R,R)-1a-CuCl2]22(AcOEt) 3, (R,R)-1a-CuCl22(THF) 4, and rac1a-CuCl2 5 were determined. These complexes were obtained from the reaction of (R,R)-1a with CuCl2, using AcOEt, THF, and MeOH as the solvents.
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Fig. 3 X-ray structure of an asymmetric unit of [(R,R)-1aCuCl2]22(AcOEt) 3 showing a bidentate structure and a distorted square-pyramidal copper coordination geometry. Ligand EtOAc hydrogen bonding geometry: N1 O1 [x, y + 1/2, z] = 3.019(2), N1–H1N = 0.84(2), H1 O1 = 2.18 (2) Å, angle N1–H1 O1 = 175(2)1; N4 O3 [x, y, z + 1] = 2.947(2), N4–H4N = 0.86(2), H4 O3 = 2.16(2) Å, angle N4–H4 O3 = 152(2)1. Scheme 1
Table 4 Catalytic asymmetric Henry reaction of benzaldehyde with nitromethane in the presence of (R,R)-1a–eCuCl2 complexesa
Entry
Ligand
Yield (%)
ee (%)
Amplificationb
1 2 3 4 5
(R,R)-1a (R,R)-1b (R,R)-1c (R,R)-1d (R,R)-1e
87 37 60 63 63
91 93 89 90 92
Yes Yes Yes No No
a
Reaction conditions: aldehyde (0.5 mmol), nitromethane (5.0 mmol), (R,R)-1 (0.05 mmol), CuCl2 (0.05 mmol), Et3N (0.05 mmol), AcOEt (1.5 mL), 0 1C, 24 h. Enantiomeric excess (ee) was determined using HPLC on a Chiralcel OD-H column. b See Fig. S4–S7.
The X-ray structures of 3, 4, and 5 provide insights into the conformational preferences of the chiral ligand [(R,R)-1a] and its coordination versatility when complexed with CuCl2. Both monoand bidentate copper coordination geometries were observed. The Cu atom in 3 was pentacoordinated and formed a bidentate coordination sphere with the apical positions occupied by Cl atoms (Fig. 3).‡ The Cu atom in the chiral complex 4 had a flattened tetrahedral coordination (Fig. 4),§ whereas nearly square-planar coordination geometry was observed in the achiral complex 5 (Fig. 5).¶ Moreover, irrespective of the Cu coordination mode the free H-atoms of the ligand amine groups served as proton donors in hydrogen bonds with solvent molecules (e.g. AcOEt or THF) in 3 and 4. In 5, the above-mentioned protons formed hydrogen bonded polymeric chains with chloride anions as shown in Fig. 6. The inability to form hydrogen bonds with solvent molecules contributes to the differences in solubility observed between chiral complexes 3 and 4 and racemic complex 5. The cyclohexane ring in each of the three complexes adopted a chair conformation. The diphenymethylamino arms were twisted outwards from the coordination sphere, allowing association with two solvent molecules or propagation of the hydrogen bonded polymeric chain. The generally accepted mechanism2c of the Henry reaction assumes
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Fig. 4 X-ray structure of [(R,R)-1aCuCl2]22(THF) 4 showing a flattened tetrahedral copper coordination geometry. Ligand THF hydrogen bonding geometry: N1 O1 = 2.959(2) [2 x, y, 2 z], N1–H = 0.83(2), H O1 = 2.13(2), Å, angle 170(2)1.
Fig. 5 X-ray structure of rac-1aCuCl2 5 with a square-planar copper coordination geometry.
simultaneous coordination of the enol form of nitromethane and benzylaldehyde to a less-hindered site because of coordination of the ligand Cu atom. Although it is not confirmed what model of Cu coordination is present in solution, it is obvious that in the case of the (R,R)-1a-CuCl2 catalyst, the coordination process is competitive to the formation of ligand–aprotic solvent hydrogen bonding. However, hydrogen bonding with the nucleophile present in the reaction mixture will be preferred.
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¶ Crystal data for the complex rac-1a-CuCl2 5: C32H34Cl2CuN2, FW = 581.05, monoclinic, space group C2/c, Z = 4, a = 25.8780(6) Å, b = 10.4574(2) Å, c = 10.7037(3) Å, b = 102.636(2)1, V = 2826.44(12) Å3, T = 150(2) K, m(CuKa) = 3.000 mm1, Dcalc = 1.365 g mm3, 8188 reflections were measured (4.581 o Y o 66.591), 2472 unique reflections (Rint = 0.0341) were corrected for numerical absorption (Tmin = 0.4948 and Tmax = 0.8744). The final R1 was 0.0431 for 2199 reflections with I 4 2s(I) and wR2 was 0.1131 (all data), GOF = 1.032. Fig. 6 Hydrogen bonded polymeric chain observed in rac-1aCuCl2 5: N1 Cl1 [x, y, z 1/2] = 3.113(2), N1–H1 = 0.87, H1 Cl1 = 2.32(2) Å, angle N1–H1 Cl1 = 170(2)1.
In conclusion, a chiral Cu(II) complex of (R,R)-1a was successfully used in the asymmetric Henry reaction. The use of this complex induced a positive nonlinear effect because of the inherent low solubility of the racemate in aprotic organic solvents such as AcOEt. The racemic 1a-CuCl2 monomer complex formed a thermodynamically more stable crystal lattice and was much less soluble in AcOEt than the enantiopure complex. This rare solid–liquid phase behavior increases the enantiomeric purity of the (R,R)-1a-CuCl2 dimer complex in the solution, and creates a large positive nonlinear effect that cannot thermodynamically control crystallization. This allows the major enantiomer in the solution to remain available for asymmetric catalysis. Studies that aim to clarify the mechanistic aspects and extension of this catalyst to other asymmetric reactions are currently underway in our laboratory. This study was supported by a Kansai University Special Research Fund, 2014.
Notes and references ‡ Crystal data for the complex [(R,R)-1a-CuCl2]22(AcOEt) 3: C72H84Cl4Cu2N4 O4, M = 1338.31, monoclinic, P21, Z = 2, a = 13.8568(3) Å, b = 15.8847(4) Å, c = 15.2073(4) Å, b = 96.0460(10)1, V = 3328.7(1) Å, T = 150(2) K, m(CuKa) = 2.664 mm1, Dcalc = 1.335 g mm3; 35 306 reflections were measured (4.041 o Y o 67.551), 9740 unique reflections (Rint = 0.0332) were corrected for experimental absorption (Tmin = 0.2045 and Tmax = 0.4627). The final R1 was 0.0270 for 9703 reflections with I 4 2s(I) and wR2 was 0.0697 (all data), GOF = 1.053. Absolute structure (Flack) parameter = 0.059(9). § Crystal data for the complex [(R,R)-1a-CuCl2]22(THF) 4: C40H50Cl2CuN2O2, FW = 725.26, monoclinic, space group C2, a = 13.608(3) Å, b = 10.347(2) Å, c = 14.528(4) Å, b = 117.341(3)1, V = 1817.1(7) Å3, T = 100(2) K, Z = 2, m(MoKa) = 0.785 mm1, 7381 reflections were measured (3.161 o Y o 27.491), 4090 independent reflections (Rint = 0.020) were corrected for experimental absorption (Tmin = 0.8401 and Tmax = 0.9048). The final R1 was 0.0224 for 3676 reflections with I 4 2s(I) and wR2 value was 0.0374 (all data), GOF = 0.866, Flack parameter = 0.017(6).
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