DOI: 10.1002/chem.201404605
Communication
& Supramolecular Catalysis | Hot Paper |
Podand-Based Dimeric Chromium(III)–Salen Complex for Asymmetric Henry Reaction: Cooperative Catalysis Promoted by Complexation of Alkali Metal Ions Guang-Hui Ouyang, Yan-Mei He,* and Qing-Hua Fan*[a] Abstract: A new kind of podand-based dimeric salen ligand was synthesized, and its association with potassium cations was investigated by 1H NMR spectroscopy. The corresponding CrIII–salen dimer was assembled by a supramolecular host–guest self-assembly process and was then used as a catalyst in highly efficient and enantioselective asymmetric Henry reactions. Regulation by KBArF (BArF = [3,5-(CF3)2C6H3]4B) led to remarkable improvements in yield (by up to 58 %) and enantioselectivity (for example, from 80 % ee to 96 % ee).
Podands, a term coined by Vçgtle and Weber in 1979,[1] refer to acyclic supramolecular hosts that contain a polyether backbone and two terminal groups. Like their cyclic counterparts, podands can form curled rigid conformations by complexation with a suitable metal cation. The terminal groups of the podands are thus brought closer together, significantly increasing their interactions.[2] Based on this conformational tunability, different kinds of allosteric systems,[3] responsive materials,[4] and other functionalized podands[5] have been successfully constructed and the efficacy and applicability of this strategy have been well demonstrated. Despite the above achievements, however, applications of podands in catalysis have rarely been reported,[6] especially for asymmetric catalysis. By coordination of podand ligands with transition metals, various metallacrown ethers have been fabricated.[7, 8] Recently, our group realized the first example of asymmetric hydrogenation catalyzed by chiral metallacrown ethers (Scheme 1), which were prepared in situ with bis(phosphite)-functionalized podands and [Rh(cod)2]BF4.[8a] The complexation of an alkali metal ion has shown remarkable effects on both catalytic activity and enantioselectivity in the asym[a] G.-H. Ouyang, Y.-M. He, Prof. Dr. Q.-H. Fan Beijing National Laboratory for Molecular Sciences CAS Key Laboratory of Molecular Recognition and Function Institute of Chemistry, Chinese Academy of Sciences (CAS) Beijing 100190 (P.R. China) and Collaborative Innovation Center of Chemical Science and Engineering Tianjin 300072 (P.R. China) E-mail: [email protected] [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404605. Chem. Eur. J. 2014, 20, 16454 – 16457
Scheme 1. Design strategies for podand-based catalysts: From metallacrown ether catalyst to cooperative metal catalyst.
metric hydrogenation of a-dehydroamino acid esters. Later, Vidal-Ferran and coworkers reported a similar chiral bis(phosphite)-containing metallacrown ether catalyst, showing tunable catalytic properties in the Rh-catalyzed asymmetric hydroformylation of terminal olefins.[8b] Although successes have been achieved in the construction of metallacrown ether catalysts by utilizing podand ligands, the direct use of functionalized podands as catalysts for efficient asymmetric catalysis has not to date been reported. As a continuation of our ongoing endeavor in developing novel and tunable catalytic systems based on supramolecular regulation, we report herein a new kind of podand catalyst bearing two separated CrIII–salen moieties for asymmetric Henry reactions. To our knowledge, this is the first example of a chiral tunable podand catalyst in asymmetric catalysis. The selection of metallosalen as the catalytic unit in the construction of this podand catalyst is based on the following considerations: 1) As the design of podand catalysts cocerns the bringing together of two podand terminals, catalytic systems involving a bimetallic cooperative catalysis mechanism will be most applicable. Metallosalen complexes are known to form this kind of catalyst.[9] 2) A number of covalently and noncovalently linked dimeric or multimetallic salen systems have been established, showing improved reactivity and enantioselectivity in compari-
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Communication son with their monomer counterparts.[10] 3) The Henry reaction is an important C C bond forming reaction, and metallosalens have proved able to catalyze this reaction in the presence of an external base[9d, 11, 12] via a bimetallic activation pathway.[10k] Therefore, we envisioned that this reaction could serve as an ideal model system to test our new podand-based bis(CrIII– salen) catalyst. Moreover, this reaction proceeds well in aprotic solvents, such as CH2Cl2, which are better solvents for the complexation between the polyether chain and an alkali metal ion. The syntheses of the target bis(salen) ligand 3 and bis(CrIII– salen) podand 4 are from easily obtained and unexpensive starting materials and are carried out according to the published methods.[10a] All of the compounds obtained are characterized by 1H and 13C NMR spectroscopy and HR-MS, and the results are in full agreement with the compounds synthesized (see the Supporting Information, section S2). With the bis(salen) ligand in hand, we first investigated the host–guest association between KBArF (BArF = [3,5(CF3)2C6H3]4B) salt and the podand bis(salen) ligand with 1 H NMR spectroscopy. In the titration experiments with CDCl3 (Figure 1), the addition of KBArF caused remarkable upfield
could bring the two podand terminals close together in the desired orientation. Having demonstrated the supramolecular association of bis(salen) podand with K + cation as we anticipated, we started to test the cooperative catalysis of podand-based bis(CrIII–salen) 4 in the Henry reaction (Table 1). 2-Methoxylbenzaldehyde was
Table 1. Asymmetric Henry reaction of 6 a catalyzed by CrIII–salen dimer 4 and Jacobsen CrIII–salen 5.[a]
Entry
Catalyst
Additive
1 2 3 4 5 6 7 8[d] 9 10 11[e]
5 5 4 4 4 4 4 4 4 4 4
No 4 mol % No 2 mol % 2 mol % 2 mol % 2 mol % 2 mol % 1 mol % 4 mol % 4 mol %
KBArF LiBArF NaBArF CsBArF KBArF KBArF KBArF KBArF KBArF
Conv. [%][b]
ee [%][c]
7 7 43 47 44 60 70 86 61 95 50
79 78 87 89 89 89 91 89 90 93 89
[a] Reaction conditions: Substrate 6 a (34 mg, 0.25 mmol), MeNO2 (152 mg, 2.5 mmol), DIPEA (4 mol % to 6 a), salen dimer 4 (2 mol % to 6 a) or Jacobsen salen 5 (4 mol % to 6 a), DCM ( 0.6 mL), 30 8C; [b] conversions are determined by 1H NMR spectroscopy; [c] ee values are determined by HPLC with a Chiralcel OD-H column; [d] DIPEA (50 mol % to 6 a); [e] crown ether 18-C-6 (4 mol % to 6 a) added. Figure 1. Stacked plot of 1H NMR spectra (600 MHz, CDCl3, 298 K, 8.8 mm): a) Salen dimer 3 + 2 equivalents of KBArF ; b) salen dimer 3 + 1 equivalent of KBArF ; c) salen dimer 3. OEG = oligo(ethylene glycol).
shifts and broadening of the signals of oxyethylene protons due to the strong shielding effect of the BArF anion,[13] indicating obvious association between K + and the podand chain. Meanwhile, signals of the aromatic protons on the phenyl groups that are linked to the polyether chain moved downfield, in a manner similar to that reported previously.[5d] Furthermore, Nonlinear data fitting[14] delivered the association constant Ka = 79 12 for binding a guest K + . This result is in accordance with the reported value.[3a] The Job plot analysis gave a 1:1 host/guest ratio (see the Supporting Information, Figure S3). These results all demonstrate that association interactions exist between bis(salen) podand and K + cation, which Chem. Eur. J. 2014, 20, 16454 – 16457
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selected as the model substrate. The podand catalyst 4 gave 43 % conversion and 87 % ee at 30 8C in 6 h (Table 1, entry 3), which are much better values than those obtained with Jacobsen CrIII–salen 5 (Table 1, entry 1). These enhancements are reasonable owing to the dimeric nature of the catalyst, which is more favorable for the bimetallic activation mechanism of salen-based catalysis.[10] The addition of KBArF had no influence on the Henry reaction catalyzed by Jacobsen CrIII–salen 5 (Table 1, entry 2; for more detailed tests, see the Supporting Information, section S4). The effects of alkali metal cations were further investigated. To our delight, in the presence of 2 mol % of alkali metal salts, increased and similar enantioselectivities were achieved for all alkali metal salts screened, whereas conversions varied extremely (Table 1, entries 4–7 vs. entry 2). Li +
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Communication and Na + cations gave conversions similar to that without an additive. In contrast, remarkable elevation in conversion was achieved by using bigger alkali metal cations; 60 % conversion was provided by Cs + and the best result of 70 % was obtained with K + cation. This size effect of alkali metal cation is plausibly due to their different level of match with the podand chain.[1] Moreover, when the amount of KBArF was increased from 2 mol % to 4 mol %, nearly quantitative conversion (95 %) was achieved (Table 1, entry 10 vs. entry 7), which is much better than those with lower amounts of K + (Only 61 % with 1 mol % KBArF ; Table 1, entry 9). These results reveal that the reactivity and enantioselectivity of the Henry reaction catalyzed by podand-based CrIII–salen dimer can be fine-tuned by selectively adding alkali metal salts. The amount of base also exhibited an obvious effect on catalytic activity, as the conversion increased from 70 % with 4 mol % of N,N-diisopropyl ethylamine (DIPEA; Table 1, entry 7) to 86 % with a slight loss of ee when 50 mol % of DIPEA was used (entry 8). It is well known that the association constant of 18-crown-6 to K + is much higher than that with a podand chain.[1a] Therefore, adding 18-crown-6 into the reaction mixture containing an assembled 4/K + catalyst leads to the disassociation of the supramolecular catalyst (Scheme 2), which was demonstrated by giving the similar conversion and ee value as those acquired
Scheme 2. K + cation-controlled allosteric podand-based dimeric CrIII–salen.
in the absence of KBArF (Table 1, entry 11 vs. entry 3). This result further reveals that the improvements of reactivity and enantioselectivity are caused by the association between the oligo(ethylene glycol) chain and K + cation. Meanwhile, the possible influence of BArF anion on the reaction is also excluded. To evaluate the scope of the Henry reaction catalyzed by podand-based CrIII–salen dimer, we applied the optimized conditions to the reactions with different substituted aromatic aldehydes (Table 2). Upon tuning with KBArF, all of the reactions proceeded smoothly with moderate to high yields (73–97 %) in 6 h, which is much faster than those reported previously for metallosalen catalysts.[9d, 10k, 11c–g] The enantioselectivities were also satisfactory and good to high ee values (83–96 % ee) were recorded, which are higher than or comparable to those reported.[9d, 10k, 11c–j, 12] More importantly, remarkable enhancements in yield and enantioselectivity were noted in the presence of K + . The highest improvement in yield for 4-fluoro-benzaldehyde Chem. Eur. J. 2014, 20, 16454 – 16457
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Table 2. Substrate scope of podand-based CrIII–salen dimer catalyzed asymmetric Henry reaction.[a]
Entry
Aldehyde
Time [h]
Yield [%][b,c]
ee [%][c,d]
1 2 3 4 5 6 7 8
R = 2-OMe, 6 a R = 2-Br, 6b R = 2-F, 6 c R = 2-Cl, 6 d R = 3-OMe, 6e R = 3-Cl, 6f R = 4-F, 6 g R = 4-Cl, 6 h
6 6 5 6 6 6 6 6
7 a: 90 (40) 7 b: 86 (54) 7 c: 97 (88) 7 d: 81 (63) 7 e: 91 (65) 7 f: 86 (54) 7 g: 85 (27) 7 h: 73 (63)
93 86 90 96 84 84 85 83
(87) (77) (81) (80) (53) (66) (77) (74)
[a] Reaction conditions: Substrate 6 (0.25 mmol), MeNO2 (152 mg, 2.5 mmol), DIPEA (4 mol % to 6), CrIII–salen 4 (2 mol % to 6), KBArF (4 mol % to 6), DCM (0.6 mL), 30 8C; [b] yield of isolated product; [c] values in parentheses are obtained in the absence of KBArF salt; [d] ee values are determined by HPLC with a Chiralcel OD-H colume or AD-H column. Absolute configurations of the major isomers are determined to be (R) by comparison of the rotation values with the literature data.
(58 %; Table 2, entry 7) was very impressive, and a 16 % improvement in entantioselectivity (from 80 % to 96 % ee for 2chloro-benzaldehyde; Table 2, entry 4) is representative of the ee elevation attained. Thus, our supramolecular strategy provides an alternative method for the synthesis of chiral nitroalcohol compounds, due to its shorter reaction time and excellent performance in Henry reactions. In summary, we have synthesized a new kind of podandbased bis(CrIII–salen) complex bearing an oligo(ethylene glycol) linkage, which has been successfully applied in asymmetric Henry reactions showing high catalytic reactivity and enantioselectivity. More importantly, it was found that the reactions could be effectively tuned by the addition of alkali metal cations. Remarkable enhancements in yield and enantioselectivity were observed in most cases. 1H NMR titration experiments and a set of control tests indicated that the host–guest association between the podand chain and potassium cation was responsible for the marked improvement in catalytic performance. To our knowledge, this study is the first example of a tunable podand catalyst used in asymmetric catalysis. Other supramolecular catalytic systems based on podands are currently under investigation.
Experimental Section General procedure for podand-based dimeric chromium(III)–salencatalyzed Henry reaction: The mixture of freshly prepared podandbased CrIII–salen dimer 4 (2 mol % with respect to aldehyde,
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Communication 7.1 mg) and KBArF (4 mol % with respect to aldehyde, 9.0 mg) in CH2Cl2 (0.5 mL) was stirred for 10 min at 30 8C, then aromatic aldehyde (0.25 mmol) and nitromethane (2.5 mmol, 0.13 mL) were added at the same temperature. The resulting mixture was stirred at this temperature for 30 min. DIPEA (0.1 mL, 0.1 m solution in CH2Cl2) was then added. After stirring for 6 h in this temperature, the product was purified by column chromatography on silica gel (eluent = 20 % ethyl acetate in n-hexane) to give the desired nitroalcohol. Enantiomeric excesses were determined by chiral HPLC analysis using Chiralcel OD-H or Chiralcel AD-H columns.
[9]
[10]
Acknowledgements Financial support from the National Basic Research Program of China (973 Program No 2011CB808600) and the National Natural Science Foundation of China (No. 21232008 and No. 21373231) are gratefully acknowledged. Keywords: asymmetric catalysis · Henry reaction · host–guest systems · podands · supramolecular catalysis [1] a) F. Vçgtle, E. Weber, Angew. Chem. 1979, 91, 534 – 549; Angew. Chem. Int. Ed. Engl. 1979, 18, 753 – 776; for books about supramolecular chemistry, see: b) J. W. Steed, J. L. Atwood, Supramolecular Chemistry, 2ednd edWiley, Chichester, 2001; c) J. M. Lehn, Supramolecular Chemistry: Concepts and Perspectives, 1edst edWiley-VCH, Weinheim, 1995; d) Supramolecular Catalysis (Ed.: P. W. N. M. van Leeuwen), Wiley-VCH, Weinheim, 2008. [2] B. Tmmler, G. Maass, F. Vçgtle, H. Sieger, U. Heimann, E. Weber, J. Am. Chem. Soc. 1979, 101, 2588 – 2598. [3] a) D. Monti, M. Venanzi, G. Mancini, F. Marotti, L. L. Monica, T. Boschi, Eur. J. Org. Chem. 1999, 1901 – 1906; b) D. Monti, L. L. Monica, A. Scipioni, G. Mancinic, New J. Chem. 2001, 25, 780 – 782. [4] a) P. S. Baran, R. R. Monaco, A. U. Khan, D. I. Schuster, S. R. Wilson, J. Am. Chem. Soc. 1997, 119, 8363 – 8364; b) H. Wu, D. Q. Zhang, L. Su, K. Ohkubo, C. X. Zhang, S. W. Yin, L. Q. Mao, Z. G. Shuai, S. Fukuzumi, D. B. Zhu, J. Am. Chem. Soc. 2007, 129, 6839 – 6846. [5] a) S. Ghosh, S. Ramakrishnan, Angew. Chem. 2004, 116, 3326 – 3330; Angew. Chem. Int. Ed. 2004, 43, 3264 – 3268; b) D. Lorcy, M. Guerro, J.-F. Bergamini, P. Hapiot, J. Phys. Chem. B 2013, 117, 5188 – 5194; c) Y. Nishimura, T. Takemura, S. Arai, Molecules 2011, 16, 6844 – 6857; d) C. H. nl, G. Yapar, C¸. Erk, Magn. Reson. Chem. 2013, 51, 42 – 45; e) M. Valente, S. F. Sousa, A. L. Magalha¯es, C. Freire, Theor. Chem. Acc. 2010, 127, 681 – 687. [6] a) H. C. Aspinall, N. Greeves, E. G. McIver, J. Alloys Compd. 1998, 275, 773 – 776; b) B. Łeska, R. Pankiewicz, G. Schroeder, A. Maia, Tetrahedron Lett. 2006, 47, 5673 – 5676. [7] For reviews on metallamacrocycles, see: a) F. C. J. M. van Veggel, W. Verboom, D. N. Reinhoubt, Chem. Rev. 1994, 94, 279 – 299; b) G. Mezei, C. M. Zaleski, V. L. Pecoraro, Chem. Rev. 2007, 107, 4933 – 5003. For recent examples of catalysis with achiral metallacrowns, see: c) S. B. Owens Jr., G. M. Gray, Organometallics 2008, 27, 4282 – 4287; d) X. Zhang, Y. Qiu, B. Rao, M. Luo, Organometallics 2009, 28, 3093 – 3099; e) A. A. Kaisare, S. B. Owens Jr., E. J. Valente, G. M. Gray, J. Organomet. Chem. 2010, 695, 2658 – 2666; f) W. Zhang, X. Zhang, M. Luo, Chin. J. Chem. 2012, 30, 1423 – 1428; g) W. Tang, W.-G. Yuan, B. Zhao, H.-L. Zhang, F. Xiong, L.-H. Jing, D.-B. Qin, J. Organomet. Chem. 2013, 743, 147 – 155. [8] For asymmetric catalysis with chiral metallacrowns, see: a) Y. Li, B. Ma, Y. He, F. Zhang, Q.-H. Fan, Chem. Asian J. 2010, 5, 2454 – 2458; b) I. Mon,
Chem. Eur. J. 2014, 20, 16454 – 16457
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[11]
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D. A. Jose, A. Vidal-Ferran, Chem. Eur. J. 2013, 19, 2720 – 2725; c) F.-T. Song, G.-H. Ouyang, Y.-M. He, Q.-H. Fan, Eur. J. Org. Chem. 2014, 6713 – 6719. For selected reviews on cooperative multimetallic catalysis using metallosalens, see: a) E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421 – 431; b) R. M. Haak, S. J. Wezenberg, A. W. Kleij, Chem. Commun. 2010, 46, 2713 – 2723; Examples for other bimetallic cooperative activation, see: c) J. A. Ma, D. Cahard, Angew. Chem. 2004, 116, 4666 – 4683; Angew. Chem. Int. Ed. 2004, 43, 4566 – 4583; d) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga, M. Shibasaki, Angew. Chem. 2008, 120, 3274 – 3277; Angew. Chem. Int. Ed. 2008, 47, 3230 – 3233. Representative strategies used for constructing dimeric or multimetallic salen systems: a) J. M. Ready, E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 2687 – 2688; b) J. M. Ready, E. N. Jacobsen, Angew. Chem. 2002, 114, 1432 – 1435; Angew. Chem. Int. Ed. 2002, 41, 1374 – 1378; c) Q. H. Yang, C. Li, Angew. Chem. 2007, 119, 6985 – 6989; Angew. Chem. Int. Ed. 2007, 46, 6861 – 6865; d) C. Mazet, E. N. Jacobsen, Angew. Chem. 2008, 120, 1786 – 1789; Angew. Chem. Int. Ed. 2008, 47, 1762 – 1765; e) M. North, Angew. Chem. 2010, 122, 8255 – 8257; Angew. Chem. Int. Ed. 2010, 49, 8079 – 8081; f) Z. P. Zhang, Z. Wang, R. Z. Zhang, K. L. Ding, Angew. Chem. 2010, 122, 6898 – 6902; Angew. Chem. Int. Ed. 2010, 49, 6746 – 6750; g) W. Clegg, R. W. Harrington, M. North, R. Pasquale, Chem. Eur. J. 2010, 16, 6828 – 6843; h) X. Zheng, M. Weck, J. Am. Chem. Soc. 2007, 129, 1105 – 1112; i) S. I. Vagin, B. Rieger, J. Am. Chem. Soc. 2010, 132, 14367 – 14369; j) R. M. Thomas, P. C. B. Widger, S. M. Ahmed, R. C. Jeske, W. Hirahata, E. B. Lobkovsky, G. W. Coates, J. Am. Chem. Soc. 2010, 132, 16520 – 16525; k) J. Park, K. Lang, K. A. Abbound, S. Hong, J. Am. Chem. Soc. 2008, 130, 16484 – 16485; l) S. Lundgren, E. Wingstrand, M. Penhoat, C. Moberg, J. Am. Chem. Soc. 2005, 127, 11592 – 11593; m) N. C. Gianneschi, P. A. Bertin, S. T. Nguyen, C. A. Mirkin, L. N. Zakharov, A. L. Rheingold, J. Am. Chem. Soc. 2003, 125, 10508 – 10509; n) A. Sadhukhan, N. H. Khan, T. Roy, R. I. Kureshy, S. H. R. Abdi, H. C. Bajaj, Chem. Eur. J. 2012, 18, 5256 – 5260. For selected reviews on the Henry reaction: a) C. Palomo, M. Oiarbide, A. Mielgo, Angew. Chem. 2004, 116, 5558 – 5560; Angew. Chem. Int. Ed. 2004, 43, 5442 – 5444; b) C. Palomo, M. Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561 – 2574. For selected examples on asymmetric Henry reaction, see: c) Y. Kogami, T. Nakajima, T. Ikeno, T. Yamada, Synthesis 2004, 12, 1947 – 1950; d) K. Lang, J. Park, S. Hong, Angew. Chem. 2012, 124, 1652 – 1656; Angew. Chem. Int. Ed. 2012, 51, 1620 – 1624; e) E. C. Constable, G. Zhang, C. E. Housecroft, M. Neuburger, S. Schaffner, W. Woggon, J. A. Zampese, New J. Chem. 2009, 33, 2166 – 2173; f) A. Das, R. Kureshy, P. S. Subramanian, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, Catal. Sci. Technol. 2014, 4, 411 – 418; g) Y. Xiong, F. Wang, X. Huang, Y. Wen, X.-M. Feng, Chem. Eur. J. 2007, 13, 829 – 833; h) H. Zhou, D. Peng, B. Qin, Z. Hou, X. Liu, X.-M. Feng, J. Org. Chem. 2007, 72, 10302 – 10304; i) B. Qin, X. Xiao, X. Liu, J. Huang, Y. Wen, X.-M. Feng, J. Org. Chem. 2007, 72, 9323 – 9328; j) C. Tan, X. Liu, L. Wang, J. Wang, X.-M. Feng, Org. Lett. 2008, 10, 5305 – 5308. For selected papers on Cr(salen)-catalyzed Henry reaction, see: a) R. Kowalczyk, Ł. Sidorowicz, J. Skarz˙ewski, Tetrahedron: Asymmetry 2007, 18, 2581 – 2586; b) R. Kowalczyk, P. Kwiatkowski, J. Skarz˙ewski, J. Jurczak, J. Org. Chem. 2009, 74, 753 – 756; c) A. Zulauf, M. Mellah, E. Schulz, J. Org. Chem. 2009, 74, 2242 – 2245; d) A. Zulauf, M. Mellah, E. Schulz, Chem. Commun. 2009, 6574 – 6576. For a review on titration experiments in supramolecular chemistry, see: P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305 – 1323. M. Inouye, T. Konishi, K. Isagawa, J. Am. Chem. Soc. 1993, 115, 8091 – 8095.
Received: July 26, 2014 Published online on October 24, 2014
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Communication
& Supramolecular Catalysis | Hot Paper |
Podand-Based Dimeric Chromium(III)–Salen Complex for Asymmetric Henry Reaction: Cooperative Catalysis Promoted by Complexation of Alkali Metal Ions Guang-Hui Ouyang, Yan-Mei He,* and Qing-Hua Fan*[a] Abstract: A new kind of podand-based dimeric salen ligand was synthesized, and its association with potassium cations was investigated by 1H NMR spectroscopy. The corresponding CrIII–salen dimer was assembled by a supramolecular host–guest self-assembly process and was then used as a catalyst in highly efficient and enantioselective asymmetric Henry reactions. Regulation by KBArF (BArF = [3,5-(CF3)2C6H3]4B) led to remarkable improvements in yield (by up to 58 %) and enantioselectivity (for example, from 80 % ee to 96 % ee).
Podands, a term coined by Vçgtle and Weber in 1979,[1] refer to acyclic supramolecular hosts that contain a polyether backbone and two terminal groups. Like their cyclic counterparts, podands can form curled rigid conformations by complexation with a suitable metal cation. The terminal groups of the podands are thus brought closer together, significantly increasing their interactions.[2] Based on this conformational tunability, different kinds of allosteric systems,[3] responsive materials,[4] and other functionalized podands[5] have been successfully constructed and the efficacy and applicability of this strategy have been well demonstrated. Despite the above achievements, however, applications of podands in catalysis have rarely been reported,[6] especially for asymmetric catalysis. By coordination of podand ligands with transition metals, various metallacrown ethers have been fabricated.[7, 8] Recently, our group realized the first example of asymmetric hydrogenation catalyzed by chiral metallacrown ethers (Scheme 1), which were prepared in situ with bis(phosphite)-functionalized podands and [Rh(cod)2]BF4.[8a] The complexation of an alkali metal ion has shown remarkable effects on both catalytic activity and enantioselectivity in the asym[a] G.-H. Ouyang, Y.-M. He, Prof. Dr. Q.-H. Fan Beijing National Laboratory for Molecular Sciences CAS Key Laboratory of Molecular Recognition and Function Institute of Chemistry, Chinese Academy of Sciences (CAS) Beijing 100190 (P.R. China) and Collaborative Innovation Center of Chemical Science and Engineering Tianjin 300072 (P.R. China) E-mail: [email protected] [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404605. Chem. Eur. J. 2014, 20, 16454 – 16457
Scheme 1. Design strategies for podand-based catalysts: From metallacrown ether catalyst to cooperative metal catalyst.
metric hydrogenation of a-dehydroamino acid esters. Later, Vidal-Ferran and coworkers reported a similar chiral bis(phosphite)-containing metallacrown ether catalyst, showing tunable catalytic properties in the Rh-catalyzed asymmetric hydroformylation of terminal olefins.[8b] Although successes have been achieved in the construction of metallacrown ether catalysts by utilizing podand ligands, the direct use of functionalized podands as catalysts for efficient asymmetric catalysis has not to date been reported. As a continuation of our ongoing endeavor in developing novel and tunable catalytic systems based on supramolecular regulation, we report herein a new kind of podand catalyst bearing two separated CrIII–salen moieties for asymmetric Henry reactions. To our knowledge, this is the first example of a chiral tunable podand catalyst in asymmetric catalysis. The selection of metallosalen as the catalytic unit in the construction of this podand catalyst is based on the following considerations: 1) As the design of podand catalysts cocerns the bringing together of two podand terminals, catalytic systems involving a bimetallic cooperative catalysis mechanism will be most applicable. Metallosalen complexes are known to form this kind of catalyst.[9] 2) A number of covalently and noncovalently linked dimeric or multimetallic salen systems have been established, showing improved reactivity and enantioselectivity in compari-
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Communication son with their monomer counterparts.[10] 3) The Henry reaction is an important C C bond forming reaction, and metallosalens have proved able to catalyze this reaction in the presence of an external base[9d, 11, 12] via a bimetallic activation pathway.[10k] Therefore, we envisioned that this reaction could serve as an ideal model system to test our new podand-based bis(CrIII– salen) catalyst. Moreover, this reaction proceeds well in aprotic solvents, such as CH2Cl2, which are better solvents for the complexation between the polyether chain and an alkali metal ion. The syntheses of the target bis(salen) ligand 3 and bis(CrIII– salen) podand 4 are from easily obtained and unexpensive starting materials and are carried out according to the published methods.[10a] All of the compounds obtained are characterized by 1H and 13C NMR spectroscopy and HR-MS, and the results are in full agreement with the compounds synthesized (see the Supporting Information, section S2). With the bis(salen) ligand in hand, we first investigated the host–guest association between KBArF (BArF = [3,5(CF3)2C6H3]4B) salt and the podand bis(salen) ligand with 1 H NMR spectroscopy. In the titration experiments with CDCl3 (Figure 1), the addition of KBArF caused remarkable upfield
could bring the two podand terminals close together in the desired orientation. Having demonstrated the supramolecular association of bis(salen) podand with K + cation as we anticipated, we started to test the cooperative catalysis of podand-based bis(CrIII–salen) 4 in the Henry reaction (Table 1). 2-Methoxylbenzaldehyde was
Table 1. Asymmetric Henry reaction of 6 a catalyzed by CrIII–salen dimer 4 and Jacobsen CrIII–salen 5.[a]
Entry
Catalyst
Additive
1 2 3 4 5 6 7 8[d] 9 10 11[e]
5 5 4 4 4 4 4 4 4 4 4
No 4 mol % No 2 mol % 2 mol % 2 mol % 2 mol % 2 mol % 1 mol % 4 mol % 4 mol %
KBArF LiBArF NaBArF CsBArF KBArF KBArF KBArF KBArF KBArF
Conv. [%][b]
ee [%][c]
7 7 43 47 44 60 70 86 61 95 50
79 78 87 89 89 89 91 89 90 93 89
[a] Reaction conditions: Substrate 6 a (34 mg, 0.25 mmol), MeNO2 (152 mg, 2.5 mmol), DIPEA (4 mol % to 6 a), salen dimer 4 (2 mol % to 6 a) or Jacobsen salen 5 (4 mol % to 6 a), DCM ( 0.6 mL), 30 8C; [b] conversions are determined by 1H NMR spectroscopy; [c] ee values are determined by HPLC with a Chiralcel OD-H column; [d] DIPEA (50 mol % to 6 a); [e] crown ether 18-C-6 (4 mol % to 6 a) added. Figure 1. Stacked plot of 1H NMR spectra (600 MHz, CDCl3, 298 K, 8.8 mm): a) Salen dimer 3 + 2 equivalents of KBArF ; b) salen dimer 3 + 1 equivalent of KBArF ; c) salen dimer 3. OEG = oligo(ethylene glycol).
shifts and broadening of the signals of oxyethylene protons due to the strong shielding effect of the BArF anion,[13] indicating obvious association between K + and the podand chain. Meanwhile, signals of the aromatic protons on the phenyl groups that are linked to the polyether chain moved downfield, in a manner similar to that reported previously.[5d] Furthermore, Nonlinear data fitting[14] delivered the association constant Ka = 79 12 for binding a guest K + . This result is in accordance with the reported value.[3a] The Job plot analysis gave a 1:1 host/guest ratio (see the Supporting Information, Figure S3). These results all demonstrate that association interactions exist between bis(salen) podand and K + cation, which Chem. Eur. J. 2014, 20, 16454 – 16457
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selected as the model substrate. The podand catalyst 4 gave 43 % conversion and 87 % ee at 30 8C in 6 h (Table 1, entry 3), which are much better values than those obtained with Jacobsen CrIII–salen 5 (Table 1, entry 1). These enhancements are reasonable owing to the dimeric nature of the catalyst, which is more favorable for the bimetallic activation mechanism of salen-based catalysis.[10] The addition of KBArF had no influence on the Henry reaction catalyzed by Jacobsen CrIII–salen 5 (Table 1, entry 2; for more detailed tests, see the Supporting Information, section S4). The effects of alkali metal cations were further investigated. To our delight, in the presence of 2 mol % of alkali metal salts, increased and similar enantioselectivities were achieved for all alkali metal salts screened, whereas conversions varied extremely (Table 1, entries 4–7 vs. entry 2). Li +
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Communication and Na + cations gave conversions similar to that without an additive. In contrast, remarkable elevation in conversion was achieved by using bigger alkali metal cations; 60 % conversion was provided by Cs + and the best result of 70 % was obtained with K + cation. This size effect of alkali metal cation is plausibly due to their different level of match with the podand chain.[1] Moreover, when the amount of KBArF was increased from 2 mol % to 4 mol %, nearly quantitative conversion (95 %) was achieved (Table 1, entry 10 vs. entry 7), which is much better than those with lower amounts of K + (Only 61 % with 1 mol % KBArF ; Table 1, entry 9). These results reveal that the reactivity and enantioselectivity of the Henry reaction catalyzed by podand-based CrIII–salen dimer can be fine-tuned by selectively adding alkali metal salts. The amount of base also exhibited an obvious effect on catalytic activity, as the conversion increased from 70 % with 4 mol % of N,N-diisopropyl ethylamine (DIPEA; Table 1, entry 7) to 86 % with a slight loss of ee when 50 mol % of DIPEA was used (entry 8). It is well known that the association constant of 18-crown-6 to K + is much higher than that with a podand chain.[1a] Therefore, adding 18-crown-6 into the reaction mixture containing an assembled 4/K + catalyst leads to the disassociation of the supramolecular catalyst (Scheme 2), which was demonstrated by giving the similar conversion and ee value as those acquired
Scheme 2. K + cation-controlled allosteric podand-based dimeric CrIII–salen.
in the absence of KBArF (Table 1, entry 11 vs. entry 3). This result further reveals that the improvements of reactivity and enantioselectivity are caused by the association between the oligo(ethylene glycol) chain and K + cation. Meanwhile, the possible influence of BArF anion on the reaction is also excluded. To evaluate the scope of the Henry reaction catalyzed by podand-based CrIII–salen dimer, we applied the optimized conditions to the reactions with different substituted aromatic aldehydes (Table 2). Upon tuning with KBArF, all of the reactions proceeded smoothly with moderate to high yields (73–97 %) in 6 h, which is much faster than those reported previously for metallosalen catalysts.[9d, 10k, 11c–g] The enantioselectivities were also satisfactory and good to high ee values (83–96 % ee) were recorded, which are higher than or comparable to those reported.[9d, 10k, 11c–j, 12] More importantly, remarkable enhancements in yield and enantioselectivity were noted in the presence of K + . The highest improvement in yield for 4-fluoro-benzaldehyde Chem. Eur. J. 2014, 20, 16454 – 16457
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Table 2. Substrate scope of podand-based CrIII–salen dimer catalyzed asymmetric Henry reaction.[a]
Entry
Aldehyde
Time [h]
Yield [%][b,c]
ee [%][c,d]
1 2 3 4 5 6 7 8
R = 2-OMe, 6 a R = 2-Br, 6b R = 2-F, 6 c R = 2-Cl, 6 d R = 3-OMe, 6e R = 3-Cl, 6f R = 4-F, 6 g R = 4-Cl, 6 h
6 6 5 6 6 6 6 6
7 a: 90 (40) 7 b: 86 (54) 7 c: 97 (88) 7 d: 81 (63) 7 e: 91 (65) 7 f: 86 (54) 7 g: 85 (27) 7 h: 73 (63)
93 86 90 96 84 84 85 83
(87) (77) (81) (80) (53) (66) (77) (74)
[a] Reaction conditions: Substrate 6 (0.25 mmol), MeNO2 (152 mg, 2.5 mmol), DIPEA (4 mol % to 6), CrIII–salen 4 (2 mol % to 6), KBArF (4 mol % to 6), DCM (0.6 mL), 30 8C; [b] yield of isolated product; [c] values in parentheses are obtained in the absence of KBArF salt; [d] ee values are determined by HPLC with a Chiralcel OD-H colume or AD-H column. Absolute configurations of the major isomers are determined to be (R) by comparison of the rotation values with the literature data.
(58 %; Table 2, entry 7) was very impressive, and a 16 % improvement in entantioselectivity (from 80 % to 96 % ee for 2chloro-benzaldehyde; Table 2, entry 4) is representative of the ee elevation attained. Thus, our supramolecular strategy provides an alternative method for the synthesis of chiral nitroalcohol compounds, due to its shorter reaction time and excellent performance in Henry reactions. In summary, we have synthesized a new kind of podandbased bis(CrIII–salen) complex bearing an oligo(ethylene glycol) linkage, which has been successfully applied in asymmetric Henry reactions showing high catalytic reactivity and enantioselectivity. More importantly, it was found that the reactions could be effectively tuned by the addition of alkali metal cations. Remarkable enhancements in yield and enantioselectivity were observed in most cases. 1H NMR titration experiments and a set of control tests indicated that the host–guest association between the podand chain and potassium cation was responsible for the marked improvement in catalytic performance. To our knowledge, this study is the first example of a tunable podand catalyst used in asymmetric catalysis. Other supramolecular catalytic systems based on podands are currently under investigation.
Experimental Section General procedure for podand-based dimeric chromium(III)–salencatalyzed Henry reaction: The mixture of freshly prepared podandbased CrIII–salen dimer 4 (2 mol % with respect to aldehyde,
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Communication 7.1 mg) and KBArF (4 mol % with respect to aldehyde, 9.0 mg) in CH2Cl2 (0.5 mL) was stirred for 10 min at 30 8C, then aromatic aldehyde (0.25 mmol) and nitromethane (2.5 mmol, 0.13 mL) were added at the same temperature. The resulting mixture was stirred at this temperature for 30 min. DIPEA (0.1 mL, 0.1 m solution in CH2Cl2) was then added. After stirring for 6 h in this temperature, the product was purified by column chromatography on silica gel (eluent = 20 % ethyl acetate in n-hexane) to give the desired nitroalcohol. Enantiomeric excesses were determined by chiral HPLC analysis using Chiralcel OD-H or Chiralcel AD-H columns.
[9]
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Received: July 26, 2014 Published online on October 24, 2014
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