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Catalytic asymmetric carbonyl–ene reaction of β,γ-unsaturated αketoesters with 5-methyleneoxazolines†
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A catalytic asymmetric carbonyl–ene reaction of β,γunsaturated α-ketoesters with 5-methyleneoxazolines was accomplished. The process was based on the utilization of a chiral N,N'-dioxide/MgII catalyst, providing the desired products with excellent outcomes (up to 99% yield, >99% ee) under mild reaction conditions. Based on the experimental investigations and previous reports, a possible transition state was proposed. The catalytic asymmetric carbonyl–ene reaction provides a powerful tool to construct versatile and useful building blocks for its atom-economical carbon–carbon bond formation.1 Since the pioneering work of Yamamoto and co-workers,2 a wide range of ene substrates, such as simple alkenes3 and highly activated ene components,4-6 have been developed to react with carbonyl compounds. However, in the intermolecular carbonyl–ene reactions, the β,γ-unsaturated α-ketoesters are not applied as carbonyl enophiles, since the inverse-electron-demand Diels– Alder reaction might be more likely to happen (Scheme 1a).7 We envisioned that when using alkylideneoxazolines as exocyclic enol ethers to react with β,γ-unsaturated α-ketoesters, 4h, 8 the aromatization of oxazolines would drive the ene reaction forward (Scheme 1b). On the other hand, the unsaturated bonds (alkene or alkyne) in the desired products allow further derivatization, and the resulting oxazole units exist in various natural products and biologically active compounds.9 Herein, as part of our continuing work on exploring chiral N,N'-dioxide/metal complexes in asymmetric catalysis,10 we wish to report the first a) Previous work
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Table 1 Optimization of the reaction conditions
R1 O
O
R1
R2O2C
CO2R2
O
O
IED hetero-DA product R1
b) This work
chiral
O
Ar
O
R1
R2O2C
O
O
MgII cat.
N
HO CO2R2 High regioselectivity
R1
High stereoselectivity More functionalization of unsaturated bonds
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N Ar
CO2R2
N O
Ar
This journal is © The Royal Society of Chemistry [year]
Entrya
Ligand
Metal
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 d
L-PiPr2 L-PiPr2 L-PiPr2 L-PiPr2 L-PrPr2 L-RaPr2 L-PiEt2 L-PiMe2 L-PiPh L-PiPr2
Cu(OTf)2 Y(OTf)3 Ni(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2
0 69 38 92 8 85 80 57 8 65
85 >99 >99 96 >99 >99 >99 57 >99
a
carbonyl-ene product
Scheme 1 Catalytic asymmetric carbonyl-ene reaction and hetero-DA reaction.
enantioselective carbonyl–ene reaction of β,γ-unsaturated αketoesters with 5-methyleneoxazolines catalyzed by a chiral N,N'dioxide/MgII complex. Initially, the methyl (E)-2-oxo-4-phenylbut-3-enoate 1a and 5methyleneoxazoline 2a were selected as the model substrates. As expected, the ene reaction was dominant when several chiral Lewis acid catalysts were tested in the presence of the N,N'dioxide ligand L-PiPr2, albeit some 1,4-adduct or the inverse electron-demand hetero-DA product were exist. As shown in Table 1, the reaction proceeded sluggishly in the presence of Cu(OTf)2 (Table 1, entry 1). When Y(OTf)3 was tested, 69% yield and 85% ee were obtained (Table 1, entry 2). It was gratifying to find that Mg(OTf)2 gave the best results in 92% yield with >99% ee, and Ni(OTf)2 afforded comparable enantioselectivity but lower yield (Table 1, entry 4 vs entry 3).
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Unless otherwise noted, the reactions were performed with 1a (0.1 mmol) and 1.3 equiv. of 2a in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d Using 5 mol % catalyst.
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Weiwei Luo,a Jiannan Zhao,a Jie Ji,a Lili Lin,a Xiaohua Liu,a Hongjiang Mei,a and Xiaoming Fenga,b*
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Table 3 Substrate scope of the reaction about 2-oxo 3-ynoates.
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Entrya 1 2 3 4 5 6 7 8 9 10 11 12
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2 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c
Yieldb (%) 92(3a) 85(3b) 87(3c) 90(3d) 92(3e) 80(3f) 91(3g) 83(3h) 73(3i) 68(3j) 86(3k) 64(3l) 93(3m) 75(3n) 90(3o) 63(3p) 98(3q) 95(3r)
eec (%) >99 (R)d >99 >99 >99 99 99 >99 >99 >99 >99 >99 >99 98 >99 >99 >99 >99 >99
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eec (%) >99 >99 (R)d 98 >99 99 >99 99 >99 >99 >99 >99 >99
Encouraged by the results of 2-oxo-3-enoates, it would be more valuable if the alkenyl group could be replaced by an alkynyl group.11 With this goal in mind, 2-oxo-3-ynoates were examined as carbonyl enophiles next. To our delight, 91-99% yields were obtained even using 5 mol% L-PiPr2-Mg(OTf)2 complex, and the enantioselectivities were also perfect for such kinds of substrates (Table 3, entries 1–12). Subsequently, simple alpha keto ester 6 and β,γ-unsaturated αketoamide 8 were also applied as enophiles to react with 2a (Scheme 2). The corresponding product 7 was obtained in 95% yield with >99% ee, while the product 9 was offered with excellent ee but in only 18% yield.
Scheme 2 Enantioselective carbonyl-ene reaction of other enophiles.
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a
Unless otherwise noted, the reactions were performed with 1 (0.1 mmol) and 1.3 equiv. of 2 in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d The absolute configuration was determined by X-ray analysis.
Yieldb (%) 99(5a) 98(5b) 91(5c) 99(5d) 99(5e) 97(5f) 90(5g) 96(5h) 92(5i) 98(5j) 99(5k) 99(5l)
Unless otherwise noted, the reactions were performed with 4 (0.1 mmol) and 1.3 equiv. of 2 in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d The absolute configuration was determined by X-ray analysis.
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1, R1, R2 1a, C6H5, Me 1b, C6H5, Et 1c, C6H5, iPr 1d, 3-ClC6H4, Me 1e, 3-MeOC6H4, Me 1f, 4-FC6H4, Me 1g, 4-ClC6H4, Me 1h, 4-BrC6H4, Me 1i, 4-MeC6H4, Me 1j, 4-MeOC6H4, Me 1k, 4-PhC6H4, Me 1l, 2,6-F2C6H3 1m, 2,6-Me2C6H3 1n, 2-naphthyl, Me 1o, 2-thienyl, Me 1p, cyhexl, Me 1a, C6H5, Me 1a, C6H5, Me
2 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c
a
Table 2 Substrate scope of the reaction about 2-oxo-3-enoates.
Entrya 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
4, R1, R2 4a, C6H5, Me 4b, C6H5, Et 4c, 3-MeC6H4, Et 4d, 4-FC6H4, Et 4e, 4-ClC6H4, Et 4f, 4-BrC6H4, Et 4g, 4-MeC6H4, Et 4h, 4-MeOC6H4, Et 4i, cyhexl, Et 4j, TMS, Et 4a, C6H5, Me 4a, C6H5, Me
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To show the synthetic utility of the catalyst system, the carbonyl–ene reaction of 2-oxo-4-phenylbut-3-ynoate 4j was expanded to a gram scale, and 5j was obtaineded in 99% yield with 99% ee (Scheme 3a). Furthermore, the product 5j could be efficiently converted into the useful 1,2-diol 10 through reduction using NaBH4.12a Meanwhile, treated with K2CO3 in EtOH to remove the TMS group,12b 5j could be easily transformed to terminal alkyne 11. Then, followed by a classical click reaction in the presence of (azidomethyl)benzene under copper(I)-mediated conditions,12c terminal alkyne 7 could be transformed to the 1,2,3triazole 12 in 95% yield and 99% ee, which exist in a wide range of pharmaceutically active compounds (Scheme 3b).13 To gain insight into the mechanism, the relationship between
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ChemComm Accepted Manuscript
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Inspired by these results, the efficiency of other N,N'-dioxide ligands was explored. As for the chiral backbone moiety, the N,N'-dioxide L-PiPr2, derived from L-pipecolic-acid, exhibited a better result than L-proline derived L-PrPr2 and L-ramipril derived L-RaPr2 (Table 1, entries 5 and 6). The steric hindrance on the phenyl ring of the ligand plays a key role in promoting both the enantioselectivity and reactivity. With a decrease in the steric hindrance of ortho-substituents on the aniline ring of the N,N'-dioxide from 2,6-diisopropyl to 2,6-diethyl and 2,6-dimethyl, the yield was decreased from 92% to 80% and 57%, respectively (Table 1, entry 4 vs entries 7 and 8). Poor results were observed by using the aniline-derived ligand L-PiPh (Table 1, entry 9). Moreover, the yield decreased to 65% but the enantioselectivity remained when the catalyst loading was reduced to 5 mol% (Table 1, entry 10). With the optimized reaction conditions in hand, we next investigated the scope of the reaction with respect to 2-oxo-3enoates, and the results were shown in Table 2. Changing the ester group in 1 from methyl to ethyl and isopropyl has no obvious influence on the reaction (Table 2, entries 1–3). Moreover, irrespective of electron-donating or electronwithdrawing substituents on the phenyl ring of the 2-oxo-3enoates, nearly optically pure products were obtained in all cases (Table 2, entries 4–13). Ring-condensed 1n and heteroaromatic 1o were also suitable substrates in the reaction (Table 2, entries 14 and 15). Notably, the reaction of 2a with γ-alkyl-substituted β,γ-unsaturated α-ketoester 1p also proceeded smoothly, giving the corresponding product in a highly enantioselective manner (Table 2, entry 16). Additionally, when 2b and 2c as nucleophiles were subjected to the reaction, the desired products were achieved in up to 98% yield with >99% ee (Table 2, entries 17 and 18).
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Scheme 3 Gram–scale synthesis and synthetic utility.
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the ee value of the ligand L-PiPr2 and that of 3a was studied.14 A linear effect was observed, which suggested that a monomeric catalyst might be the main catalytic active species. In light of the X-ray structure of 3a and 5b,15 as well as our previous work,4g a proposed catalytic model was illustrated in Figure 1. The methyl (E)-2-oxo-4-phenylbut-3-enoate 1a could coordinate to the MgII in a bidentate fashion with its dicarbonyl groups. The Re face of the methyl (E)-2-oxo-4-phenylbut-3-enoate 1a was shielded by the neighboring 2,6-diisopropylphenyl group of the ligand, and the nucleophile 2a attacked from the Si face predominantly to give the R-configured product.
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Fig. 1 Proposed activation model and the absolute configuration of 3a.
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Conclusions
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In summary, we have developed a highly efficient catalytic asymmetric carbonyl–ene reaction of β,γ-unsaturated α-ketoesters with 5-methyleneoxazolines in the presence of a chiral N,N'dioxide/MgII complex. A series of chiral α-hydroxyesters bearing a quaternary center were obtained in good to excellent yields with excellent enantioselectivities. The utility of this methodology is highlighted by the gram-scale synthesis and the useful conversions. Additional studies of applying this catalyst to other reactions are underway. We appreciate the National Natural Science Foundation of China (Nos. 21172151, 21321061 and 21432006) for financial support.
Notes and references This journal is © The Royal Society of Chemistry [year]
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Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China. E-mail: [email protected]; Fax: + 86 28 85418249; Tel: + 86 28 85418249 b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) † Electronic Supplementary Information (ESI) available: Addiitional experimental and spectroscopic data. See DOI:10.1039/b000000x/ 1 For selected reviews, see: (a) K. Mikami and M. Shimizu, Chem. Rev., 1992, 92, 1021; (b) K. Mikami, Pure Appl. Chem., 1996, 68, 639; (c) L. C. Dias, Curr. Org. Chem., 2000, 4, 305; (d) M. L. Clarke and M. B. France, Tetrahedron, 2008, 64, 9003; (e) X. H. Liu, K. Zheng and X. M. Feng, Synthesis, 2014, 46, 2241. 2 K. Maruoka, Y. Hoshino, T. Shirasaka and H. Yamamoto, Tetrahedron Lett., 1988, 29, 3967. 3 (a) K. Mikami, M. Terada and T. Nakai, J. Am. Chem. Soc., 1989, 111, 1940; (b) D. A. Evans, C. S. Burgey, N. A. Paras, T. Vojkovsky and S. W. Tregay, J. Am. Chem. Soc., 1998, 120, 5824; (c) Y. Yuan, X. Zhang and K. Ding, Angew. Chem., Int. Ed., 2003, 42, 5478; (d) D. A. Evans and J. Wu, J. Am. Chem. Soc., 2005, 127, 8006; (e) M. Rueping, T. Theissmann, A. Kuenkel, and R. M. Koenigs, Angew. Chem., Int. Ed., 2008, 47, 6798; (f) K. Zheng, J. Shi, X. H. Liu and X. M. Feng, J. Am.Chem. Soc., 2008, 130, 15770; (g) J. -F. Zhao, H. -Y. Tsui, P. -J. Wu, J. Lu and T. -P. Loh, J. Am. Chem. Soc., 2008, 130, 16492; (h) P. M. Truong, P. Y. Zavalij and M. P. Doyle, Angew. Chem., Int. Ed., 2014, 53, 6468. 4 (a) K. Mikami and S. Matsukawa, J. Am. Chem. Soc., 1993, 115, 7039; (b) E. M. Carreira, W. Lee and R. A. Singer, J. Am. Chem. Soc., 1995, 117, 3649; (c) R. T. Ruck and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 2882; (d) R. T. Ruck and E. N. Jacobsen, Angew. Chem., Int. Ed., 2003, 42, 4771; (e) K. Mikami, Y. Kawakami, K. Akiyama and K. Aikawa, J. Am. Chem. Soc., 2007, 129, 12950; (f) K. Aikawa, S. Mimura, Y. Numata and K. Mikami, Eur. J. Org. Chem., 2011, 62; (g) K. Zheng, C. K. Yin, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2011, 50, 2573; (h) W. W. Luo, J. N. Zhao, C. K. Yin, X. H. Liu, L. L. Lin and X. M. Feng, Chem. Commun., 2014, 50, 7524. 5 (a) R. Matsubara, Y. Nakamura and S. Kobayashi, Angew. Chem., Int. Ed., 2004, 43, 3258; (b) R. Matsubara, P. Vital, Y. Nakamura, H. Kiyohara and S. Kobayashi, Tetrahedron, 2004, 60, 9769; (c) J. S. Fossey, R. Matsubara, P. Vital and S. Kobayashi, Org. Biomol. Chem., 2005, 3, 2910; (d) M. Terada, K. Soga and N. Momiyama, Angew. Chem., Int. Ed., 2008, 47, 4122; (e) K. Zheng, X. H. Liu, J. N. Zhao, Y. Yang, L. L. Lin and X. M. Feng, Chem. Commun., 2010, 46, 3771. 6 (a) A. Crespo-Peña, D. Monge, E. Martín-Zamora, E. Álvarez, R. Fernández and J. M. Lassaletta, J. Am. Chem. Soc., 2012, 134, 12912; (b) D. Monge, A. M. Crespo-Peña, E. Martín-Zamora, E. Álvarez, R. Fernández and J. M. Lassaletta, Chem. – Eur. J., 2013, 19, 8421. 7 For reviews, see: (a) X. Jiang and R. Wang, Chem. Rev., 2013, 113, 5515; (b) G. Desimoni, G. Faita, and P. Quadrelli, Chem. Rev., 2013, 113, 5924; for selected examples, see:(c) D. A. Evans and J. S. Johnson, J. Am. Chem. Soc., 1998, 120, 4895; (d) J. Thorhauge, M. Johannsen and K. A. Jørgensen, Angew. Chem., Int. Ed., 1998, 37, 2404; (e) W. Zhuang, J. Thorhauge and K. A. Jørgensen, Chem. Commun., 2000, 459; (f) Y. Zhu, M. S. Xie, S. X. Dong, X. H. Zhao, L. L. Lin, X. H. Liu and X. M. Feng, Chem. – Eur. J., 2011, 17, 8202, (g) J. Lv, L. Zhang, S. Luo and J.-P. Cheng, Angew. Chem., Int. Ed., 2013, 52, 9786; (h) Y. Matsumura, T. Suzuki, A. Sakakura and K. Ishihara, Angew. Chem., Int. Ed., 2014, 53, 6131; (i) Y. H. Zhou, Y. Zhu, L. L. Lin, Y. L. Zhang, J. F. Zheng, X. H. Liu and X. M. Feng, Chem. – Eur. J., 2014, 20, 16753. 8 (a) W. H. Miles, E. A. Dethoff, H. H. Tuson and G. Ulas, J. Org. Chem., 2005, 70, 2862; (b) A. S. K. Hashmi and A. Littmann, Chem. – Asian J., 2012, 7, 143; (c) G. H. Liang, D. T. Sharum, T. Lam and N. I. Totah, Org. Lett., 2013, 15, 5974. 9 For selected reviews, see: (a) P. Wipf, Chem. Rev., 1995, 95, 2115; (b) The Chemistry of Heterocyclic Compounds: Oxazoles: Synthesis, Reactions, and Spectroscopy, Parts A & B, ed. D. C. Palmer, Wiley, Hoboken, 2004, vol. 60; (c) V. S. C. Yeh,
Journal Name, [year], [vol], 00–00 | 3
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Tetrahedron, 2004, 60, 11995; (d) Z. Jin, Nat. Prod. Rep., 2013, 30, 869. (a) X. H. Liu, L. L. Lin and X. M. Feng, Acc. Chem. Res., 2011, 44, 574; (b) X. H. Liu, L. L. Lin and X. M. Feng, Org. Chem. Front., 2014, 1, 298; (c) J. N. Zhao, B. Fang, W. W. Luo, X. Y. Hao, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2015, 54, 241; (d) W. Li, F. Tan, X. Y. Hao, G. Wang, Y. Tang, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2015, 54, 1608. M. Guo, D. Li and Z. Zhang, J. Org. Chem., 2003, 68, 10172. (a) K. Aikawa, Y. Hioki and K. Mikami, Org. Lett., 2010, 12, 5716; (b) F. Shi, S.-W. Luo, Z.-L. Tao, L. He, J. Yu, S.-J. Tu and L.-Z. Gong, Org. Lett., 2011, 13, 4680; (c) X. Liang, C.-J. Lee, J. Zhao, E. J. Toone and P. Zhou, J. Med. Chem., 2013, 56, 6954. (a) J. E. Moses and A. D. Moorhouse, Chem. Soc. Rev., 2007, 36, 1249; (b) E. Lallana, R. Riguera and E. Fernandez-Megia, Angew. Chem., Int. Ed., 2011, 50, 8794. See ESI† for details. CCDC 1046971 (3a) and 1047008 (5b).
This journal is © The Royal Society of Chemistry [year]
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Luo, J. Zhao, J. Ji, L. Lin, X. Liu, H. Mei and X. Feng, Chem. Commun., 2015, DOI: 10.1039/C5CC02748A.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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DOI: 10.1039/C5CC02748A
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Catalytic asymmetric carbonyl–ene reaction of β,γ-unsaturated αketoesters with 5-methyleneoxazolines†
5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A catalytic asymmetric carbonyl–ene reaction of β,γunsaturated α-ketoesters with 5-methyleneoxazolines was accomplished. The process was based on the utilization of a chiral N,N'-dioxide/MgII catalyst, providing the desired products with excellent outcomes (up to 99% yield, >99% ee) under mild reaction conditions. Based on the experimental investigations and previous reports, a possible transition state was proposed. The catalytic asymmetric carbonyl–ene reaction provides a powerful tool to construct versatile and useful building blocks for its atom-economical carbon–carbon bond formation.1 Since the pioneering work of Yamamoto and co-workers,2 a wide range of ene substrates, such as simple alkenes3 and highly activated ene components,4-6 have been developed to react with carbonyl compounds. However, in the intermolecular carbonyl–ene reactions, the β,γ-unsaturated α-ketoesters are not applied as carbonyl enophiles, since the inverse-electron-demand Diels– Alder reaction might be more likely to happen (Scheme 1a).7 We envisioned that when using alkylideneoxazolines as exocyclic enol ethers to react with β,γ-unsaturated α-ketoesters, 4h, 8 the aromatization of oxazolines would drive the ene reaction forward (Scheme 1b). On the other hand, the unsaturated bonds (alkene or alkyne) in the desired products allow further derivatization, and the resulting oxazole units exist in various natural products and biologically active compounds.9 Herein, as part of our continuing work on exploring chiral N,N'-dioxide/metal complexes in asymmetric catalysis,10 we wish to report the first a) Previous work
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Table 1 Optimization of the reaction conditions
R1 O
O
R1
R2O2C
CO2R2
O
O
IED hetero-DA product R1
b) This work
chiral
O
Ar
O
R1
R2O2C
O
O
MgII cat.
N
HO CO2R2 High regioselectivity
R1
High stereoselectivity More functionalization of unsaturated bonds
35
N Ar
CO2R2
N O
Ar
This journal is © The Royal Society of Chemistry [year]
Entrya
Ligand
Metal
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 d
L-PiPr2 L-PiPr2 L-PiPr2 L-PiPr2 L-PrPr2 L-RaPr2 L-PiEt2 L-PiMe2 L-PiPh L-PiPr2
Cu(OTf)2 Y(OTf)3 Ni(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2 Mg(OTf)2
0 69 38 92 8 85 80 57 8 65
85 >99 >99 96 >99 >99 >99 57 >99
a
carbonyl-ene product
Scheme 1 Catalytic asymmetric carbonyl-ene reaction and hetero-DA reaction.
enantioselective carbonyl–ene reaction of β,γ-unsaturated αketoesters with 5-methyleneoxazolines catalyzed by a chiral N,N'dioxide/MgII complex. Initially, the methyl (E)-2-oxo-4-phenylbut-3-enoate 1a and 5methyleneoxazoline 2a were selected as the model substrates. As expected, the ene reaction was dominant when several chiral Lewis acid catalysts were tested in the presence of the N,N'dioxide ligand L-PiPr2, albeit some 1,4-adduct or the inverse electron-demand hetero-DA product were exist. As shown in Table 1, the reaction proceeded sluggishly in the presence of Cu(OTf)2 (Table 1, entry 1). When Y(OTf)3 was tested, 69% yield and 85% ee were obtained (Table 1, entry 2). It was gratifying to find that Mg(OTf)2 gave the best results in 92% yield with >99% ee, and Ni(OTf)2 afforded comparable enantioselectivity but lower yield (Table 1, entry 4 vs entry 3).
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Unless otherwise noted, the reactions were performed with 1a (0.1 mmol) and 1.3 equiv. of 2a in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d Using 5 mol % catalyst.
[journal], [year], [vol], 00–00 | 1
ChemComm Accepted Manuscript
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Weiwei Luo,a Jiannan Zhao,a Jie Ji,a Lili Lin,a Xiaohua Liu,a Hongjiang Mei,a and Xiaoming Fenga,b*
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Table 3 Substrate scope of the reaction about 2-oxo 3-ynoates.
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Entrya 1 2 3 4 5 6 7 8 9 10 11 12
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2 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c
Yieldb (%) 92(3a) 85(3b) 87(3c) 90(3d) 92(3e) 80(3f) 91(3g) 83(3h) 73(3i) 68(3j) 86(3k) 64(3l) 93(3m) 75(3n) 90(3o) 63(3p) 98(3q) 95(3r)
eec (%) >99 (R)d >99 >99 >99 99 99 >99 >99 >99 >99 >99 >99 98 >99 >99 >99 >99 >99
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eec (%) >99 >99 (R)d 98 >99 99 >99 99 >99 >99 >99 >99 >99
Encouraged by the results of 2-oxo-3-enoates, it would be more valuable if the alkenyl group could be replaced by an alkynyl group.11 With this goal in mind, 2-oxo-3-ynoates were examined as carbonyl enophiles next. To our delight, 91-99% yields were obtained even using 5 mol% L-PiPr2-Mg(OTf)2 complex, and the enantioselectivities were also perfect for such kinds of substrates (Table 3, entries 1–12). Subsequently, simple alpha keto ester 6 and β,γ-unsaturated αketoamide 8 were also applied as enophiles to react with 2a (Scheme 2). The corresponding product 7 was obtained in 95% yield with >99% ee, while the product 9 was offered with excellent ee but in only 18% yield.
Scheme 2 Enantioselective carbonyl-ene reaction of other enophiles.
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a
Unless otherwise noted, the reactions were performed with 1 (0.1 mmol) and 1.3 equiv. of 2 in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d The absolute configuration was determined by X-ray analysis.
Yieldb (%) 99(5a) 98(5b) 91(5c) 99(5d) 99(5e) 97(5f) 90(5g) 96(5h) 92(5i) 98(5j) 99(5k) 99(5l)
Unless otherwise noted, the reactions were performed with 4 (0.1 mmol) and 1.3 equiv. of 2 in CH2Cl2 (1.0 mL) at 30 oC for 30 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase. d The absolute configuration was determined by X-ray analysis.
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1, R1, R2 1a, C6H5, Me 1b, C6H5, Et 1c, C6H5, iPr 1d, 3-ClC6H4, Me 1e, 3-MeOC6H4, Me 1f, 4-FC6H4, Me 1g, 4-ClC6H4, Me 1h, 4-BrC6H4, Me 1i, 4-MeC6H4, Me 1j, 4-MeOC6H4, Me 1k, 4-PhC6H4, Me 1l, 2,6-F2C6H3 1m, 2,6-Me2C6H3 1n, 2-naphthyl, Me 1o, 2-thienyl, Me 1p, cyhexl, Me 1a, C6H5, Me 1a, C6H5, Me
2 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c
a
Table 2 Substrate scope of the reaction about 2-oxo-3-enoates.
Entrya 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
4, R1, R2 4a, C6H5, Me 4b, C6H5, Et 4c, 3-MeC6H4, Et 4d, 4-FC6H4, Et 4e, 4-ClC6H4, Et 4f, 4-BrC6H4, Et 4g, 4-MeC6H4, Et 4h, 4-MeOC6H4, Et 4i, cyhexl, Et 4j, TMS, Et 4a, C6H5, Me 4a, C6H5, Me
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To show the synthetic utility of the catalyst system, the carbonyl–ene reaction of 2-oxo-4-phenylbut-3-ynoate 4j was expanded to a gram scale, and 5j was obtaineded in 99% yield with 99% ee (Scheme 3a). Furthermore, the product 5j could be efficiently converted into the useful 1,2-diol 10 through reduction using NaBH4.12a Meanwhile, treated with K2CO3 in EtOH to remove the TMS group,12b 5j could be easily transformed to terminal alkyne 11. Then, followed by a classical click reaction in the presence of (azidomethyl)benzene under copper(I)-mediated conditions,12c terminal alkyne 7 could be transformed to the 1,2,3triazole 12 in 95% yield and 99% ee, which exist in a wide range of pharmaceutically active compounds (Scheme 3b).13 To gain insight into the mechanism, the relationship between
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Inspired by these results, the efficiency of other N,N'-dioxide ligands was explored. As for the chiral backbone moiety, the N,N'-dioxide L-PiPr2, derived from L-pipecolic-acid, exhibited a better result than L-proline derived L-PrPr2 and L-ramipril derived L-RaPr2 (Table 1, entries 5 and 6). The steric hindrance on the phenyl ring of the ligand plays a key role in promoting both the enantioselectivity and reactivity. With a decrease in the steric hindrance of ortho-substituents on the aniline ring of the N,N'-dioxide from 2,6-diisopropyl to 2,6-diethyl and 2,6-dimethyl, the yield was decreased from 92% to 80% and 57%, respectively (Table 1, entry 4 vs entries 7 and 8). Poor results were observed by using the aniline-derived ligand L-PiPh (Table 1, entry 9). Moreover, the yield decreased to 65% but the enantioselectivity remained when the catalyst loading was reduced to 5 mol% (Table 1, entry 10). With the optimized reaction conditions in hand, we next investigated the scope of the reaction with respect to 2-oxo-3enoates, and the results were shown in Table 2. Changing the ester group in 1 from methyl to ethyl and isopropyl has no obvious influence on the reaction (Table 2, entries 1–3). Moreover, irrespective of electron-donating or electronwithdrawing substituents on the phenyl ring of the 2-oxo-3enoates, nearly optically pure products were obtained in all cases (Table 2, entries 4–13). Ring-condensed 1n and heteroaromatic 1o were also suitable substrates in the reaction (Table 2, entries 14 and 15). Notably, the reaction of 2a with γ-alkyl-substituted β,γ-unsaturated α-ketoester 1p also proceeded smoothly, giving the corresponding product in a highly enantioselective manner (Table 2, entry 16). Additionally, when 2b and 2c as nucleophiles were subjected to the reaction, the desired products were achieved in up to 98% yield with >99% ee (Table 2, entries 17 and 18).
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Scheme 3 Gram–scale synthesis and synthetic utility.
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the ee value of the ligand L-PiPr2 and that of 3a was studied.14 A linear effect was observed, which suggested that a monomeric catalyst might be the main catalytic active species. In light of the X-ray structure of 3a and 5b,15 as well as our previous work,4g a proposed catalytic model was illustrated in Figure 1. The methyl (E)-2-oxo-4-phenylbut-3-enoate 1a could coordinate to the MgII in a bidentate fashion with its dicarbonyl groups. The Re face of the methyl (E)-2-oxo-4-phenylbut-3-enoate 1a was shielded by the neighboring 2,6-diisopropylphenyl group of the ligand, and the nucleophile 2a attacked from the Si face predominantly to give the R-configured product.
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Fig. 1 Proposed activation model and the absolute configuration of 3a.
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Conclusions
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In summary, we have developed a highly efficient catalytic asymmetric carbonyl–ene reaction of β,γ-unsaturated α-ketoesters with 5-methyleneoxazolines in the presence of a chiral N,N'dioxide/MgII complex. A series of chiral α-hydroxyesters bearing a quaternary center were obtained in good to excellent yields with excellent enantioselectivities. The utility of this methodology is highlighted by the gram-scale synthesis and the useful conversions. Additional studies of applying this catalyst to other reactions are underway. We appreciate the National Natural Science Foundation of China (Nos. 21172151, 21321061 and 21432006) for financial support.
Notes and references This journal is © The Royal Society of Chemistry [year]
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Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China. E-mail: [email protected]; Fax: + 86 28 85418249; Tel: + 86 28 85418249 b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) † Electronic Supplementary Information (ESI) available: Addiitional experimental and spectroscopic data. See DOI:10.1039/b000000x/ 1 For selected reviews, see: (a) K. Mikami and M. Shimizu, Chem. Rev., 1992, 92, 1021; (b) K. Mikami, Pure Appl. Chem., 1996, 68, 639; (c) L. C. Dias, Curr. Org. Chem., 2000, 4, 305; (d) M. L. Clarke and M. B. France, Tetrahedron, 2008, 64, 9003; (e) X. H. Liu, K. Zheng and X. M. Feng, Synthesis, 2014, 46, 2241. 2 K. Maruoka, Y. Hoshino, T. Shirasaka and H. Yamamoto, Tetrahedron Lett., 1988, 29, 3967. 3 (a) K. Mikami, M. Terada and T. Nakai, J. Am. Chem. Soc., 1989, 111, 1940; (b) D. A. Evans, C. S. Burgey, N. A. Paras, T. Vojkovsky and S. W. Tregay, J. Am. Chem. Soc., 1998, 120, 5824; (c) Y. Yuan, X. Zhang and K. Ding, Angew. Chem., Int. Ed., 2003, 42, 5478; (d) D. A. Evans and J. Wu, J. Am. Chem. Soc., 2005, 127, 8006; (e) M. Rueping, T. Theissmann, A. Kuenkel, and R. M. Koenigs, Angew. Chem., Int. Ed., 2008, 47, 6798; (f) K. Zheng, J. Shi, X. H. Liu and X. M. Feng, J. Am.Chem. Soc., 2008, 130, 15770; (g) J. -F. Zhao, H. -Y. Tsui, P. -J. Wu, J. Lu and T. -P. Loh, J. Am. Chem. Soc., 2008, 130, 16492; (h) P. M. Truong, P. Y. Zavalij and M. P. Doyle, Angew. Chem., Int. Ed., 2014, 53, 6468. 4 (a) K. Mikami and S. Matsukawa, J. Am. Chem. Soc., 1993, 115, 7039; (b) E. M. Carreira, W. Lee and R. A. Singer, J. Am. Chem. Soc., 1995, 117, 3649; (c) R. T. Ruck and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 2882; (d) R. T. Ruck and E. N. Jacobsen, Angew. Chem., Int. Ed., 2003, 42, 4771; (e) K. Mikami, Y. Kawakami, K. Akiyama and K. Aikawa, J. Am. Chem. Soc., 2007, 129, 12950; (f) K. Aikawa, S. Mimura, Y. Numata and K. Mikami, Eur. J. Org. Chem., 2011, 62; (g) K. Zheng, C. K. Yin, X. H. Liu, L. L. Lin and X. M. Feng, Angew. Chem., Int. Ed., 2011, 50, 2573; (h) W. W. Luo, J. N. Zhao, C. K. Yin, X. H. Liu, L. L. Lin and X. M. Feng, Chem. Commun., 2014, 50, 7524. 5 (a) R. Matsubara, Y. Nakamura and S. Kobayashi, Angew. Chem., Int. Ed., 2004, 43, 3258; (b) R. Matsubara, P. Vital, Y. Nakamura, H. Kiyohara and S. Kobayashi, Tetrahedron, 2004, 60, 9769; (c) J. S. Fossey, R. Matsubara, P. Vital and S. Kobayashi, Org. Biomol. Chem., 2005, 3, 2910; (d) M. Terada, K. Soga and N. Momiyama, Angew. Chem., Int. Ed., 2008, 47, 4122; (e) K. Zheng, X. H. Liu, J. N. Zhao, Y. Yang, L. L. Lin and X. M. Feng, Chem. Commun., 2010, 46, 3771. 6 (a) A. Crespo-Peña, D. Monge, E. Martín-Zamora, E. Álvarez, R. Fernández and J. M. Lassaletta, J. Am. Chem. Soc., 2012, 134, 12912; (b) D. Monge, A. M. Crespo-Peña, E. Martín-Zamora, E. Álvarez, R. Fernández and J. M. Lassaletta, Chem. – Eur. J., 2013, 19, 8421. 7 For reviews, see: (a) X. Jiang and R. Wang, Chem. Rev., 2013, 113, 5515; (b) G. Desimoni, G. Faita, and P. Quadrelli, Chem. Rev., 2013, 113, 5924; for selected examples, see:(c) D. A. Evans and J. S. Johnson, J. Am. Chem. Soc., 1998, 120, 4895; (d) J. Thorhauge, M. Johannsen and K. A. Jørgensen, Angew. Chem., Int. Ed., 1998, 37, 2404; (e) W. Zhuang, J. Thorhauge and K. A. Jørgensen, Chem. Commun., 2000, 459; (f) Y. Zhu, M. S. Xie, S. X. Dong, X. H. Zhao, L. L. Lin, X. H. Liu and X. M. Feng, Chem. – Eur. J., 2011, 17, 8202, (g) J. Lv, L. Zhang, S. Luo and J.-P. Cheng, Angew. Chem., Int. Ed., 2013, 52, 9786; (h) Y. Matsumura, T. Suzuki, A. Sakakura and K. Ishihara, Angew. Chem., Int. Ed., 2014, 53, 6131; (i) Y. H. Zhou, Y. Zhu, L. L. Lin, Y. L. Zhang, J. F. Zheng, X. H. Liu and X. M. Feng, Chem. – Eur. J., 2014, 20, 16753. 8 (a) W. H. Miles, E. A. Dethoff, H. H. Tuson and G. Ulas, J. Org. Chem., 2005, 70, 2862; (b) A. S. K. Hashmi and A. Littmann, Chem. – Asian J., 2012, 7, 143; (c) G. H. Liang, D. T. Sharum, T. Lam and N. I. Totah, Org. Lett., 2013, 15, 5974. 9 For selected reviews, see: (a) P. Wipf, Chem. Rev., 1995, 95, 2115; (b) The Chemistry of Heterocyclic Compounds: Oxazoles: Synthesis, Reactions, and Spectroscopy, Parts A & B, ed. D. C. Palmer, Wiley, Hoboken, 2004, vol. 60; (c) V. S. C. Yeh,
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