DOI: 10.1002/chem.201500833
Communication
& Synthetic Methods
Scandium-Catalyzed Asymmetric 1,6-Addition of 3-Substituted Oxindoles to Linear Dienyl Ketones Zhen Wang,[a] Tengfei Kang,[a] Qian Yao,[a] Jie Ji,[a] Xiaohua Liu,[a] Lili Lin,[a] and Xiaoming Feng*[a, b] Abstract: The first example of a N,N’-dioxide–ScIII-catalyzed 1,6-addition of 3-substituted oxindoles to dienyl ketones has been developed. This procedure tolerates a relatively wide range of 3-substituted oxindoles under mild conditions, facilitating the preparation of various chiral oxindoles with quaternary stereocenters. In addition, the reliable catalyst was found to be effective in the asymmetric 1,6-addition of both d-unsubstituted and d-methyl-substituted dienyl ketones, achieving excellent regioselectivities and enantioselectivities (up to > 99 % ee). Scheme 1. Metal-complex-catalyzed 1,6-addition of carbon nucleophiles to dienyl carbonyl compounds.
The asymmetric conjugate addition of carbon nucleophiles to vinylogous electron-deficient dienes constitutes one of the most versatile synthetic methodologies for the construction of optically active carbonyl compounds.[1] However, the asymmetric 1,6-addition at the d-position of electron-deficient dienes is still challenging.[2, 3] This may result from the difficulty in controlling the regioselectivity and the competing 1,4-addition owing to the high reactivity at the b-position of the dienes. Hayashi and co-workers have reported the use of transition metals such as rhodium and iridium to catalyze the 1,6-addition of aryl boroxines and aryl zinc reagents.[4] Chiral copper complexes were developed by Feringa, Alexakis, and Fillion et al. for the asymmetric 1,6-addition of organometallic reagents to dienones and dienoates.[5, 6] In addition, several examples of organocatalytic 1,6-addition reactions have been reported by Jørgensen, Melchiorre, and Ooi et al.[7] Despite these impressive contributions in the field of regioselective 1,6-additions, lanthanide complexes have not been developed for this asymmetric transformation. Herein, we report the first example of a N,N’-dioxide–ScIII-catalyzed 1,6-addition of 3-substituted oxindoles to d-unsubstituted dienyl ketones and d-methyl-substituted dienyl ketones with excellent enantioselectivities and
regioselectivities, giving optically active chiral oxindoles with quaternary stereocenters (Scheme 1).[8, 9] In a preliminary study, we examined the asymmetric 1,6-addition of 3-benzyloxindole (1 a) to d-unsubstituted dienyl ketone 2 a promoted by Sc(OTf)3–N,N’-dioxide complexes under air.[10] Fortunately, in the presence of 2,6-diisopropylphenyl-derived N,N’-dioxides, the desired 1,6-addition product 3 a was obtained in moderate yields with good enantioselectivities (92–96 % ee, Table 1, entries 1–3). The results also showed that for the chiral backbone moiety, l-ramipril acid derived lRaPr2 was superior to l-proline derived l-PrPr2 and (S)-pipecolic acid derived l-PiPr2 with regard to enantioselectivity (Table 1, entry 3 vs. entries 1 and 2). The ee value could be improved to 97 % ee by using CHCl3 instead of CH2Cl2 as the solvent (Table 1, entry 4). Furthermore, this process is also tolerant to air and moisture, since the reactivity and enantioselectivity were maintained in the presence of water (Table 1, entry 5). Subsequently, the asymmetric 1,6-addition of 3-benzyloxindole (1 a) to d-methyl-substituted dienyl ketone 3 a was explored (Table 1, entries 6–11). The reaction proceeded smoothly to afford the desired 1,6-adduct 5 a with excellent enantioselectivity, albeit with moderate diastereoselectivity (97 % ee, 70:30 d.r., Table 1, entry 6). Interestingly, it was found that N,N’-dioxide–GdIII complexes gave the opposite configuration of product 5 a in excellent enantioselectivities with moderate diastereoselectivities (up to 95 % ee, 63:37 d.r., Table 1, entries 7 and 8), even in the presence of the same ligand (Table 1, entry 7 vs. entry 6).[11] Encouraged by these results, further optimizations of the reaction conditions were then carried out. A solvent screening indicated that a higher diastereoselectivity could be obtained in THF than in CHCl3 and CH2Cl2, with a retention of the enantioselectivity (Table 1, entry 10 vs.
[a] Z. Wang, T. Kang, Q. Yao, J. Ji, Prof. Dr. X. Liu, L. Lin, Prof. Dr. X. Feng Key Laboratory of Green Chemistry & Technology Ministry of Education, College of Chemistry Sichuan University, Chengdu 610064 (P. R. China) Fax: (+ 86) 28-8541-8249 E-mail: [email protected] [b] Prof. Dr. X. Feng Collaborative Innovation Centre of Chemical Science and Engineering Tianjin 300000 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500833. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Optimization of the 1,6-addition of 3-benzyloxindole (1 a) to linear 2,4-dienones under air.[a]
Entry
Ligand
Xa
Yield [%][b]
ee [%][c]
d.r.[c]
1 2 3 4[d] 5[d,e] 6[d] 7[d,g] 8[d,g] 9 10[i] 11[i,j]
l-PrPr2 l-PiPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-PiPr2 l-RaPr2 l-RaPr2 l-RaPr2
2a 2a 2a 2a 2a 3a 3a 3a 3a 3a 3a
72 63 68 67 67 85 85 62 86 78 83
94 92 96 97 97 97[f] 90[f,h] 95[f,h] 97[f] 98[f] > 99[f]
– – – – – 70:30 79:21 63:37 65:35 85:15 > 95:5[k]
(4 a) (4 a) (4 a) (4 a) (4 a) (5 a) (5 a) (5 a) (5 a) (5 a) (5 a)
Table 2. Substrate scope of the 1,6-addition of 3-substituted oxindoles to d-unsubstituted dienyl ketones under air.[a]
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Yield [%][b]
ee [%][c]
1 2 3 4 5 6 7 8 9 10 11 12 13 14[d] 15[d] 16[d] 17[d]
H, Bn H, Bn H, 3-BrC6H4CH2 H, 3-NO2C6H4CH2 H, 3-MeC6H4CH2 H, 4-BrC6H4CH2 H, 4-CNC6H4CH2 H, 4-MeOC6H4CH2 H, 2,4-Cl2C6H3CH2 H, 2-naphthylmethyl H, 2-thienylmethyl H, 2-furanylmethyl H, Me H, Ph Me, Ph H, 4-ClC6H4 H, 2-naphthyl
2a 2b 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a
67 63 72 79 63 79 81 68 76 85 80 84 80 89 81 93 80
97 95 96 96 97 96 96 98 96 96 99 98 92 94 (S)[e] 93 93 93
(4 a) (4 b) (4 c) (4 d) (4 e) (4 f) (4 g) (4 h) (4 i) (4 j) (4 k) (4 l) (4 m) (4 n) (4 o) (4 p) (4 q)
applicable, affording the corresponding products 4 j–l in 80– 85 % yield with excellent enantioselectivities (96–99 % ee, Table 2, entries 10–12). In addition, 3-methyloxindole also reacted well, generating the desired product 4 m in 80 % yield with 92 % ee (Table 2, entry 13). To our delight, after a slight modification of the catalyst system by altering the solvent from chloroform to acidic chloroform (see the Supporting Information for details), good yields and excellent enantioselectivities were obtained for 3-aryloxindoles as well. The electronic properties of the substituent on the aromatic ring of the 3-aryloxindoles had no obvious effect on the enantioselectivity of the reaction (93–94 % ee, Table 2, entries 14–16). A 3-aryloxindole bearing a condensed ring also proved suitable with respect to the enantioselectivity of the reaction (Table 2, entry 17). In addition, ozonolysis of the 1,6-adduct 4 n followed by benzylation and reduction in the presence of BnBr and NaBH4 furnished chiral compound 6 without any loss of enantioselectivity (Scheme 2 A).[12] Finally, the absolute configuration of 4 n was determined to be S by comparison with the literature data of its derivative 6.[13] Given the remarkable performance of the present catalyst system in the highly selective 1,6-addition of d-unsubstituted dienyl ketones, the 1,6-addition of d-methyl-substituted dienyl ketones was also examined. Under the optimal reaction conditions (Table 1, entry 9), with d-methyldienyl ketone 3 a as electrophilic substrate,[14] various 3-alkyloxindoles oxindoles were
entries 6 and 9). To our delight, when K3PO4·7 H2O was used as the basic additive instead of Na2CO3, the 1,6-addition reaction proceeded smoothly while maintaining exclusive enantioselectivity and excellent diastereoselectivity (> 99 % ee, > 95:5 d.r., Table 1, entry 11). Under the optimal conditions (Table 1, entry 4), the scope of the 1,6-addition of d-unsubstituted dienyl ketones with a series of oxindoles 1 was investigated (Table 2). First, an investigation of the effect of the Ar1 group of d-unsubstituted dienyl ketones showed that the electronic properties of the substituents on the aromatic ring only had little effect on the enantioselectivity of the reaction; the corresponding 1,6-adducts were obtained with 95–97 % ee (Table 2, entries 1 and 2). Then, a series of 3-alkyloxindoles were examined (Table 2, entries 3–13). In general, the reactions proceeded well, giving good yields (63–85 %) and excellent levels of enantioselectivities (92–99 % ee). Both the electronic nature and the position of the substituents at the aromatic ring of R2 had a limited influence on the enantioselectivity (96–98 % ee, Table 2, entries 3–9). When substrates containing electron-donating substituent were used, slightly reduced yields were obtained (Table 2, entries 5 and 8). Moreover, substrates bearing a condensed-ring or heteroaromatic-ring substituent as R2 were also &
1: R1, R2
[a] Unless otherwise noted, reactions were carried out with l-RaPr2 (6 mol %), Sc(OTf)3 (5 mol %), 1 (0.10 mmol), 2 (0.12 mmol), Na2CO3 (0.1 mmol), and MS (4 , 50 mg) in CHCl3 (1.0 mL) at 30 8C for 5 h. [b] Isolated yield of 4. [c] Determined by chiral HPLC analysis. [d] Acidic chloroform was used as solvent (please see the Supporting Information for details). [e] The absolute configuration of 4 n was determined by comparison with the literature data of its derivative 6.
[a] Unless otherwise noted, reactions were carried out with ligand (6 mol %), Sc(OTf)3 (5 mol %), 1 a (0.10 mmol), 2 a or 3 a (0.12 mmol), Na2CO3 (0.1 mmol), and MS (4 , 50 mg) in CH2Cl2 (1.0 mL) at 30 8C for 5– 20 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis (l = 254 nm). [d] CHCl3 was used as solvent. [e] The reaction was performed in the presence of H2O (10 mL). [f] The ee value refers to the major isomer. [g] Gd(OTf)3 was used instead of Sc(OTf)3. [h] The ee value of the opposite configuration is defined as minus. [i] THF was used as solvent. [j] K3PO4·7 H2O was used as basic additive. [k] The d.r. was determined to be > 95:5 by 1H NMR analysis.
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Figure 1. Proposed model for the transition state.
complexes as catalysts, a plausible transition-state model was proposed. As illustrated in Figure 1, the carbonyl group of the 3-substituted oxindole coordinates to the l-RaPr2–ScIII complex to form an enolate. Meanwhile, dienyl ketone 2 a coordinates to ScIII at the favorable position.[15] Subsequently, the re face of enolate attacks the d-position of the dienyl ketone, affording the corresponding 1,6-adduct 4 n with S configuration. In summary, we have successfully developed a scandium(III) complex to catalyze the asymmetric 1,6-addition of 3-substituted oxindoles to d-unsubstituted and d-methyl-substituted dienyl ketone, achieving excellent enantiomeric and regioselective control (up to > 99 % ee, > 95:5 d.r.). In particular, the procedure tolerates a relatively wide range of substrates under mild conditions, giving optically active chiral oxindoles with quaternary stereocenters.
Scheme 2. A) Determination of the absolute configuration of 4 n by transformation to 6. B) Scaled-up version of the 1,6-addition of oxindole 1 a to 3 a.
Table 3. Substrate scope of the 1,6-addition of 3-substituted oxindoles to d-methyl-substituted dienyl ketone 3 a under air.[a]
entry
1: R1
Yield [%][b]
d.r.[c]
ee[%][d]
1 2 3 4 5 6 7 8
Bn 3-MeC6H4CH2 3-BrC6H4CH2 4-BrC6H4CH2 4-MeOC6H4CH2 2-naphthylmethyl 2-thienylmethyl Me
83 74 80 74 78 87 80 72
> 95:5 > 95:5 95:5 95:5 > 95:5 > 95:5 > 95:5 90:10
> 99 > 99 99 > 99 > 99 > 99 > 99 > 99
(5 a) (5 b) (5 c) (5 d) (5 e) (5 f) (5 g) (5 h)
Experimental Section Typical experimental procedure for the 1,6-addition reaction of 3-alkyoxindoles to d-unsubstituted dienyl ketones N,N’-Dioxide–l-RaPr2 (4.2 mg, 0.006 mmol), scandium triflate (2.5 mg, 0.005 mmol), 3-benzyloxindole 1 a (22.3 mg, 0.10 mmol), and 4 molecular sieves (50.0 mg) were stirred in a dry reaction tube in CHCl3 (1.0 mL) at 30 8C for 10 min; then, d-unsubstituted dienyl ketone 2 a (22.6 mg, 0.12 mmol) and Na2CO3 (10.6 mg, 0.1 mmol) were added. The reaction mixture was stirred at 30 8C for 5 h and then purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5:1 to 3:1) to afford the desired product 4 a in 67 % (27.5 mg, 0.067 mmol) yield with 97 % ee.
[a] Unless otherwise noted, reactions were carried out with l-RaPr2 (6 mol %), Sc(OTf)3 (5 mol %), 1 (0.10 mmol), 3 a (0.12 mmol), K3PO4·7 H2O (0.1 mmol), and MS (4 , 50 mg) in THF (1.0 mL) at 30 8C for 20 h. [b] Isolated yield. [c] Determined by 1H NMR analysis. [d] Determined by chiral HPLC analysis.
examined. Both the electronic properties and the steric hindrance of the substituent at the R1 group had no obvious effect on the enantioselectivity and diastereoselectivity of the reaction (generally > 99 % ee, 95:5 d.r., Table 3, entries 1–7). Fortunately, excellent enantioselectivity (> 99 % ee) and good diastereoselectivity (90:10 d.r.) was also observed for the 3methyloxindole substrate (Table 3, entry 8). To further extend the application of the present approach, a large-scale synthesis of 5 a was performed. As shown in Scheme 2 B, by reacting 4.5 mmol of starting material 1 a with 3 a under the optimal reaction conditions in the presence of only 3.3 % mol of the lRaPr2–ScIII complex, the desired product 5 a was produced in 81 % yield (1.58 g) with > 99 % ee and 93:7 d.r. On the basis of the observed absolute configuration of enantiopure 4 n and previous reports using N,N’-dioxide–ScIII Chem. Eur. J. 2015, 21, 1 – 5
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Acknowledgements We acknowledge the National Natural Science Foundation of China (Nos. 21372162, 21432006, 21321061) and the National Basic Research Program of China (973 Program: No. 2011CB808600) for financial support. Keywords: 1,6-addition reaction · asymmetric catalysis · diastereoselectivity · N,N’-dioxides · scandium [1] For reviews on conjugate addition reactions, see: a) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Pergamon, Oxford, 1992; b) Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New York, 1999; c) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; d) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
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Chem. 2002, 1877; e) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev. 2005, 105, 933; f) D. Almas¸i, D. A. Alonso, C. Njera, Tetrahedron: Asymmetry 2007, 18, 299; g) S. Sulzer-Moss, A. Alexakis, Chem. Commun. 2007, 3123. For reviews on asymmetric 1,6-addition reactions, see: a) A. G. Csky¨, G. de La Herrn, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080; b) A. T. Biju, ChemCatChem 2011, 3, 1847; c) E. M. P. Silva, A. M. S. Silva, Synthesis 2012, 3109; d) M. J. Lear, Y. Hayashi, ChemCatChem 2013, 5, 3499. For examples of 1,6-addition reactions with heteronucleophiles, see: a) K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898; b) X. Tian, Y. Liu, P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 6439; Angew. Chem. 2012, 124, 6545; c) J. Z. Lu, J. X. Ye, W. L. Duan, Chem. Commun. 2014, 50, 698. For examples of rhodium- and iridium-catalyzed 1,6-addition reactions, see: a) T. Hayashi, S. Yamamoto, N. Tokunaga, Angew. Chem. Int. Ed. 2005, 44, 4224; Angew. Chem. 2005, 117, 4296; b) T. Nishimura, Y. Yasuhara, T. Hayashi, Angew. Chem. Int. Ed. 2006, 45, 5164; Angew. Chem. 2006, 118, 5288; c) T. Nishimura, Y. Yasuhara, T. Sawano, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 7872; d) T. Nishimura, A. Noishiki, T. Hayashi, Chem. Commun. 2012, 48, 973; e) T. Nishimura, Y. Yasuhara, T. Sawano, T. Hayashi, J. Am. Chem. Soc. 2010, 132, 12865. For examples of copper-catalyzed asymmetric 1,6-addition reactions, see: a) E. Fillion, A. Wilsily, E. T. Liao, Tetrahedron: Asymmetry 2006, 17, 2957; b) T. den Hartog, S. R. Harutyunyan, D. Font, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed. 2008, 47, 398; Angew. Chem. 2008, 120, 404; c) H. Hnon, M. Mauduit, A. Alexakis, Angew. Chem. Int. Ed. 2008, 47, 9122; Angew. Chem. 2008, 120, 9262; d) M. Tissot, D. Mller, S. Belot, A. Alexakis, Org. Lett. 2010, 12, 2770; e) J. Wencel-Delord, A. Alexakis, C. Crvisy, M. Mauduit, Org. Lett. 2010, 12, 4335; f) M. Tissot, D. Poggiali, H. Hnon, D. Mller, L. Gune, M. Mauduit, A. Alexakis, Chem. Eur. J. 2012, 18, 8731. For one example of an iron-catalyzed 1,6-addition of dienoates with a chiral auxiliary, see: S. Okada, K. Arayama, R. Murayama, T. Ishizuka, K. Hara, N. Hirone, T. Hata, H. Urabe, Angew. Chem. Int. Ed. 2008, 47, 6860; Angew. Chem. 2008, 120, 6966. For examples of organocatalyzed asymmetric 1,6-addition reactions, see: a) L. Bernardi, J. Jesffls Lpez-Cantarero, B. Niess, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772; b) J. J. Murphy, A. Quintard, P. McArdle, A. Alexakis, J. C. Stephens, Angew. Chem. Int. Ed. 2011, 50, 5095; Angew. Chem. 2011, 123, 5201; c) H. W. Sun, Y. H. Liao, Z. J. Wu, H.-Y. Wang, X. M. Zhang, W. C. Yuan, Tetrahedron 2011, 67, 3991; d) D. Uraguchi, K. Yoshioka, Y. Ueki, T. Ooi, J. Am. Chem. Soc. 2012, 134, 19370; e) L. Dell’Amico, Ł. Albrecht, T. Naicker, P. H. Poulsen, K. A. Jørgensen, J. Am. Chem. Soc. 2013, 135, 8063. For reviews on transformations with 3-substituted oxindoles, see: a) R. M. Williams, R. J. Cox, Acc. Chem. Res. 2003, 36, 127; b) A. B.
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Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945; c) H. Lin, S. J. Danishefsky, Angew. Chem. Int. Ed. 2003, 42, 36; Angew. Chem. 2003, 115, 38; d) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209; e) C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46, 8748; Angew. Chem. 2007, 119, 8902; f) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003; g) F. Zhou, Y. L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381; h) K. Shen, X. H. Liu, L. L. Lin, X. M. Feng, Chem. Sci. 2012, 3, 327. For reviews on the catalytic enantioselective construction of quaternary chiral centers, see: a) J. Christoffers, A. Baro, Angew. Chem. Int. Ed. 2003, 42, 1688; Angew. Chem. 2003, 115, 1726; b) E. A. Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 11943; c) D. J. Ramon, M. Yus, Curr. Org. Chem. 2004, 8, 149; d) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473. For reviews on chiral N-oxides in asymmetric catalysis, see: a) X. M. Feng, X. H. Liu in Scandium: Compounds, Productions and Applications (Ed.: V. A. Greene), Nova Science, New York, 2011, pp. 1 – 48; b) X. H. Liu, L. L. Lin, X. M. Feng, Acc. Chem. Res. 2011, 44, 574; c) A. V. Malkov, P. Kocˇovsky´, Eur. J. Org. Chem. 2007, 29; d) G. Chelucci, G. Murineddu, G. A. Pinna, Tetrahedron: Asymmetry 2004, 15, 1373; for our recent work in this field, see: e) W. Li, X. H. Liu, X. Y. Hao, X. L. Hu, Y. Y. Chu, W. D. Cao, S. Qin, C. W. Hu, L. L. Lin, X. M. Feng, J. Am. Chem. Soc. 2011, 133, 15268; f) Z. Wang, Z. G. Yang, D. H. Chen, X. H. Liu, L. L. Lin, X. M. Feng, Angew. Chem. Int. Ed. 2011, 50, 4928; Angew. Chem. 2011, 123, 5030; g) M. S. Xie, X. H. Chen, Y. Zhu, B. Gao, L. L. Lin, X. H. Liu, X. M. Feng, Angew. Chem. Int. Ed. 2010, 49, 3799; Angew. Chem. 2010, 122, 3887; h) Y. F. Cai, X. H. Liu, Y. H. Hui, J. Jiang, W. T. Wang, W. L. Chen, L. L. Lin, X. M. Feng, Angew. Chem. Int. Ed. 2010, 49, 6160; Angew. Chem. 2010, 122, 6296. Please see the Supporting Information for details. For similar examples, see: a) G. Desimoni, G. Faita, M. Guala, C. Pratelli, J. Org. Chem. 2003, 68, 7862; b) G. Desimoni, G. Faita, M. Guala, A. Laurenti, M. Mella, Chem. Eur. J. 2005, 11, 3816; also see reference [10g]. Please see the Supporting Information for details. a) R. He, C. Ding, K. Maruoka, Angew. Chem. Int. Ed. 2009, 48, 4559; Angew. Chem. 2009, 121, 4629; b) A. B. Dounay, K. Hatanaka, J. J. Kodanko, M. Oestreich, L. E. Overman, L. A. Pfeifer, M. W. Weiss, J. Am. Chem. Soc. 2003, 125, 6261. For d-substitutents other than methyl, there still exists a low reactivity and difficulty in separating the pure products. T. C. Wabnitz, J.-Q. Yu, J. B. Spencer, Chem. Eur. J. 2004, 10, 484.
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COMMUNICATION & Synthetic Methods Z. Wang, T. Kang, Q. Yao, J. Ji, X. Liu, L. Lin, X. Feng* && – && A highly enantioselective 1,6-addition of 3-substituted oxindoles to linear dienylketones has been developed by using a chiral N,N’-dioxide–scandium(III) complex. This reliable catalyst was found to be effective in the asymmetric
Chem. Eur. J. 2015, 21, 1 – 5
1,6-addition of both d-unsubstituted and d-methyl-substituted dienyl ketones to give excellent regioselectivities (up to 95:5 d.r.) and enantioselectivities (up to > 99 % ee).
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Scandium-Catalyzed Asymmetric 1,6Addition of 3-Substituted Oxindoles to Linear Dienyl Ketones
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Scandium-Catalyzed Asymmetric 1,6-Addition of 3-Substituted Oxindoles to Linear Dienyl Ketones Zhen Wang,[a] Tengfei Kang,[a] Qian Yao,[a] Jie Ji,[a] Xiaohua Liu,[a] Lili Lin,[a] and Xiaoming Feng*[a, b] Abstract: The first example of a N,N’-dioxide–ScIII-catalyzed 1,6-addition of 3-substituted oxindoles to dienyl ketones has been developed. This procedure tolerates a relatively wide range of 3-substituted oxindoles under mild conditions, facilitating the preparation of various chiral oxindoles with quaternary stereocenters. In addition, the reliable catalyst was found to be effective in the asymmetric 1,6-addition of both d-unsubstituted and d-methyl-substituted dienyl ketones, achieving excellent regioselectivities and enantioselectivities (up to > 99 % ee). Scheme 1. Metal-complex-catalyzed 1,6-addition of carbon nucleophiles to dienyl carbonyl compounds.
The asymmetric conjugate addition of carbon nucleophiles to vinylogous electron-deficient dienes constitutes one of the most versatile synthetic methodologies for the construction of optically active carbonyl compounds.[1] However, the asymmetric 1,6-addition at the d-position of electron-deficient dienes is still challenging.[2, 3] This may result from the difficulty in controlling the regioselectivity and the competing 1,4-addition owing to the high reactivity at the b-position of the dienes. Hayashi and co-workers have reported the use of transition metals such as rhodium and iridium to catalyze the 1,6-addition of aryl boroxines and aryl zinc reagents.[4] Chiral copper complexes were developed by Feringa, Alexakis, and Fillion et al. for the asymmetric 1,6-addition of organometallic reagents to dienones and dienoates.[5, 6] In addition, several examples of organocatalytic 1,6-addition reactions have been reported by Jørgensen, Melchiorre, and Ooi et al.[7] Despite these impressive contributions in the field of regioselective 1,6-additions, lanthanide complexes have not been developed for this asymmetric transformation. Herein, we report the first example of a N,N’-dioxide–ScIII-catalyzed 1,6-addition of 3-substituted oxindoles to d-unsubstituted dienyl ketones and d-methyl-substituted dienyl ketones with excellent enantioselectivities and
regioselectivities, giving optically active chiral oxindoles with quaternary stereocenters (Scheme 1).[8, 9] In a preliminary study, we examined the asymmetric 1,6-addition of 3-benzyloxindole (1 a) to d-unsubstituted dienyl ketone 2 a promoted by Sc(OTf)3–N,N’-dioxide complexes under air.[10] Fortunately, in the presence of 2,6-diisopropylphenyl-derived N,N’-dioxides, the desired 1,6-addition product 3 a was obtained in moderate yields with good enantioselectivities (92–96 % ee, Table 1, entries 1–3). The results also showed that for the chiral backbone moiety, l-ramipril acid derived lRaPr2 was superior to l-proline derived l-PrPr2 and (S)-pipecolic acid derived l-PiPr2 with regard to enantioselectivity (Table 1, entry 3 vs. entries 1 and 2). The ee value could be improved to 97 % ee by using CHCl3 instead of CH2Cl2 as the solvent (Table 1, entry 4). Furthermore, this process is also tolerant to air and moisture, since the reactivity and enantioselectivity were maintained in the presence of water (Table 1, entry 5). Subsequently, the asymmetric 1,6-addition of 3-benzyloxindole (1 a) to d-methyl-substituted dienyl ketone 3 a was explored (Table 1, entries 6–11). The reaction proceeded smoothly to afford the desired 1,6-adduct 5 a with excellent enantioselectivity, albeit with moderate diastereoselectivity (97 % ee, 70:30 d.r., Table 1, entry 6). Interestingly, it was found that N,N’-dioxide–GdIII complexes gave the opposite configuration of product 5 a in excellent enantioselectivities with moderate diastereoselectivities (up to 95 % ee, 63:37 d.r., Table 1, entries 7 and 8), even in the presence of the same ligand (Table 1, entry 7 vs. entry 6).[11] Encouraged by these results, further optimizations of the reaction conditions were then carried out. A solvent screening indicated that a higher diastereoselectivity could be obtained in THF than in CHCl3 and CH2Cl2, with a retention of the enantioselectivity (Table 1, entry 10 vs.
[a] Z. Wang, T. Kang, Q. Yao, J. Ji, Prof. Dr. X. Liu, L. Lin, Prof. Dr. X. Feng Key Laboratory of Green Chemistry & Technology Ministry of Education, College of Chemistry Sichuan University, Chengdu 610064 (P. R. China) Fax: (+ 86) 28-8541-8249 E-mail: [email protected] [b] Prof. Dr. X. Feng Collaborative Innovation Centre of Chemical Science and Engineering Tianjin 300000 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500833. Chem. Eur. J. 2015, 21, 1 – 5
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Communication Table 1. Optimization of the 1,6-addition of 3-benzyloxindole (1 a) to linear 2,4-dienones under air.[a]
Entry
Ligand
Xa
Yield [%][b]
ee [%][c]
d.r.[c]
1 2 3 4[d] 5[d,e] 6[d] 7[d,g] 8[d,g] 9 10[i] 11[i,j]
l-PrPr2 l-PiPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-RaPr2 l-PiPr2 l-RaPr2 l-RaPr2 l-RaPr2
2a 2a 2a 2a 2a 3a 3a 3a 3a 3a 3a
72 63 68 67 67 85 85 62 86 78 83
94 92 96 97 97 97[f] 90[f,h] 95[f,h] 97[f] 98[f] > 99[f]
– – – – – 70:30 79:21 63:37 65:35 85:15 > 95:5[k]
(4 a) (4 a) (4 a) (4 a) (4 a) (5 a) (5 a) (5 a) (5 a) (5 a) (5 a)
Table 2. Substrate scope of the 1,6-addition of 3-substituted oxindoles to d-unsubstituted dienyl ketones under air.[a]
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Yield [%][b]
ee [%][c]
1 2 3 4 5 6 7 8 9 10 11 12 13 14[d] 15[d] 16[d] 17[d]
H, Bn H, Bn H, 3-BrC6H4CH2 H, 3-NO2C6H4CH2 H, 3-MeC6H4CH2 H, 4-BrC6H4CH2 H, 4-CNC6H4CH2 H, 4-MeOC6H4CH2 H, 2,4-Cl2C6H3CH2 H, 2-naphthylmethyl H, 2-thienylmethyl H, 2-furanylmethyl H, Me H, Ph Me, Ph H, 4-ClC6H4 H, 2-naphthyl
2a 2b 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a
67 63 72 79 63 79 81 68 76 85 80 84 80 89 81 93 80
97 95 96 96 97 96 96 98 96 96 99 98 92 94 (S)[e] 93 93 93
(4 a) (4 b) (4 c) (4 d) (4 e) (4 f) (4 g) (4 h) (4 i) (4 j) (4 k) (4 l) (4 m) (4 n) (4 o) (4 p) (4 q)
applicable, affording the corresponding products 4 j–l in 80– 85 % yield with excellent enantioselectivities (96–99 % ee, Table 2, entries 10–12). In addition, 3-methyloxindole also reacted well, generating the desired product 4 m in 80 % yield with 92 % ee (Table 2, entry 13). To our delight, after a slight modification of the catalyst system by altering the solvent from chloroform to acidic chloroform (see the Supporting Information for details), good yields and excellent enantioselectivities were obtained for 3-aryloxindoles as well. The electronic properties of the substituent on the aromatic ring of the 3-aryloxindoles had no obvious effect on the enantioselectivity of the reaction (93–94 % ee, Table 2, entries 14–16). A 3-aryloxindole bearing a condensed ring also proved suitable with respect to the enantioselectivity of the reaction (Table 2, entry 17). In addition, ozonolysis of the 1,6-adduct 4 n followed by benzylation and reduction in the presence of BnBr and NaBH4 furnished chiral compound 6 without any loss of enantioselectivity (Scheme 2 A).[12] Finally, the absolute configuration of 4 n was determined to be S by comparison with the literature data of its derivative 6.[13] Given the remarkable performance of the present catalyst system in the highly selective 1,6-addition of d-unsubstituted dienyl ketones, the 1,6-addition of d-methyl-substituted dienyl ketones was also examined. Under the optimal reaction conditions (Table 1, entry 9), with d-methyldienyl ketone 3 a as electrophilic substrate,[14] various 3-alkyloxindoles oxindoles were
entries 6 and 9). To our delight, when K3PO4·7 H2O was used as the basic additive instead of Na2CO3, the 1,6-addition reaction proceeded smoothly while maintaining exclusive enantioselectivity and excellent diastereoselectivity (> 99 % ee, > 95:5 d.r., Table 1, entry 11). Under the optimal conditions (Table 1, entry 4), the scope of the 1,6-addition of d-unsubstituted dienyl ketones with a series of oxindoles 1 was investigated (Table 2). First, an investigation of the effect of the Ar1 group of d-unsubstituted dienyl ketones showed that the electronic properties of the substituents on the aromatic ring only had little effect on the enantioselectivity of the reaction; the corresponding 1,6-adducts were obtained with 95–97 % ee (Table 2, entries 1 and 2). Then, a series of 3-alkyloxindoles were examined (Table 2, entries 3–13). In general, the reactions proceeded well, giving good yields (63–85 %) and excellent levels of enantioselectivities (92–99 % ee). Both the electronic nature and the position of the substituents at the aromatic ring of R2 had a limited influence on the enantioselectivity (96–98 % ee, Table 2, entries 3–9). When substrates containing electron-donating substituent were used, slightly reduced yields were obtained (Table 2, entries 5 and 8). Moreover, substrates bearing a condensed-ring or heteroaromatic-ring substituent as R2 were also &
1: R1, R2
[a] Unless otherwise noted, reactions were carried out with l-RaPr2 (6 mol %), Sc(OTf)3 (5 mol %), 1 (0.10 mmol), 2 (0.12 mmol), Na2CO3 (0.1 mmol), and MS (4 , 50 mg) in CHCl3 (1.0 mL) at 30 8C for 5 h. [b] Isolated yield of 4. [c] Determined by chiral HPLC analysis. [d] Acidic chloroform was used as solvent (please see the Supporting Information for details). [e] The absolute configuration of 4 n was determined by comparison with the literature data of its derivative 6.
[a] Unless otherwise noted, reactions were carried out with ligand (6 mol %), Sc(OTf)3 (5 mol %), 1 a (0.10 mmol), 2 a or 3 a (0.12 mmol), Na2CO3 (0.1 mmol), and MS (4 , 50 mg) in CH2Cl2 (1.0 mL) at 30 8C for 5– 20 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis (l = 254 nm). [d] CHCl3 was used as solvent. [e] The reaction was performed in the presence of H2O (10 mL). [f] The ee value refers to the major isomer. [g] Gd(OTf)3 was used instead of Sc(OTf)3. [h] The ee value of the opposite configuration is defined as minus. [i] THF was used as solvent. [j] K3PO4·7 H2O was used as basic additive. [k] The d.r. was determined to be > 95:5 by 1H NMR analysis.
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Figure 1. Proposed model for the transition state.
complexes as catalysts, a plausible transition-state model was proposed. As illustrated in Figure 1, the carbonyl group of the 3-substituted oxindole coordinates to the l-RaPr2–ScIII complex to form an enolate. Meanwhile, dienyl ketone 2 a coordinates to ScIII at the favorable position.[15] Subsequently, the re face of enolate attacks the d-position of the dienyl ketone, affording the corresponding 1,6-adduct 4 n with S configuration. In summary, we have successfully developed a scandium(III) complex to catalyze the asymmetric 1,6-addition of 3-substituted oxindoles to d-unsubstituted and d-methyl-substituted dienyl ketone, achieving excellent enantiomeric and regioselective control (up to > 99 % ee, > 95:5 d.r.). In particular, the procedure tolerates a relatively wide range of substrates under mild conditions, giving optically active chiral oxindoles with quaternary stereocenters.
Scheme 2. A) Determination of the absolute configuration of 4 n by transformation to 6. B) Scaled-up version of the 1,6-addition of oxindole 1 a to 3 a.
Table 3. Substrate scope of the 1,6-addition of 3-substituted oxindoles to d-methyl-substituted dienyl ketone 3 a under air.[a]
entry
1: R1
Yield [%][b]
d.r.[c]
ee[%][d]
1 2 3 4 5 6 7 8
Bn 3-MeC6H4CH2 3-BrC6H4CH2 4-BrC6H4CH2 4-MeOC6H4CH2 2-naphthylmethyl 2-thienylmethyl Me
83 74 80 74 78 87 80 72
> 95:5 > 95:5 95:5 95:5 > 95:5 > 95:5 > 95:5 90:10
> 99 > 99 99 > 99 > 99 > 99 > 99 > 99
(5 a) (5 b) (5 c) (5 d) (5 e) (5 f) (5 g) (5 h)
Experimental Section Typical experimental procedure for the 1,6-addition reaction of 3-alkyoxindoles to d-unsubstituted dienyl ketones N,N’-Dioxide–l-RaPr2 (4.2 mg, 0.006 mmol), scandium triflate (2.5 mg, 0.005 mmol), 3-benzyloxindole 1 a (22.3 mg, 0.10 mmol), and 4 molecular sieves (50.0 mg) were stirred in a dry reaction tube in CHCl3 (1.0 mL) at 30 8C for 10 min; then, d-unsubstituted dienyl ketone 2 a (22.6 mg, 0.12 mmol) and Na2CO3 (10.6 mg, 0.1 mmol) were added. The reaction mixture was stirred at 30 8C for 5 h and then purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5:1 to 3:1) to afford the desired product 4 a in 67 % (27.5 mg, 0.067 mmol) yield with 97 % ee.
[a] Unless otherwise noted, reactions were carried out with l-RaPr2 (6 mol %), Sc(OTf)3 (5 mol %), 1 (0.10 mmol), 3 a (0.12 mmol), K3PO4·7 H2O (0.1 mmol), and MS (4 , 50 mg) in THF (1.0 mL) at 30 8C for 20 h. [b] Isolated yield. [c] Determined by 1H NMR analysis. [d] Determined by chiral HPLC analysis.
examined. Both the electronic properties and the steric hindrance of the substituent at the R1 group had no obvious effect on the enantioselectivity and diastereoselectivity of the reaction (generally > 99 % ee, 95:5 d.r., Table 3, entries 1–7). Fortunately, excellent enantioselectivity (> 99 % ee) and good diastereoselectivity (90:10 d.r.) was also observed for the 3methyloxindole substrate (Table 3, entry 8). To further extend the application of the present approach, a large-scale synthesis of 5 a was performed. As shown in Scheme 2 B, by reacting 4.5 mmol of starting material 1 a with 3 a under the optimal reaction conditions in the presence of only 3.3 % mol of the lRaPr2–ScIII complex, the desired product 5 a was produced in 81 % yield (1.58 g) with > 99 % ee and 93:7 d.r. On the basis of the observed absolute configuration of enantiopure 4 n and previous reports using N,N’-dioxide–ScIII Chem. Eur. J. 2015, 21, 1 – 5
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Acknowledgements We acknowledge the National Natural Science Foundation of China (Nos. 21372162, 21432006, 21321061) and the National Basic Research Program of China (973 Program: No. 2011CB808600) for financial support. Keywords: 1,6-addition reaction · asymmetric catalysis · diastereoselectivity · N,N’-dioxides · scandium [1] For reviews on conjugate addition reactions, see: a) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Pergamon, Oxford, 1992; b) Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New York, 1999; c) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; d) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
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COMMUNICATION & Synthetic Methods Z. Wang, T. Kang, Q. Yao, J. Ji, X. Liu, L. Lin, X. Feng* && – && A highly enantioselective 1,6-addition of 3-substituted oxindoles to linear dienylketones has been developed by using a chiral N,N’-dioxide–scandium(III) complex. This reliable catalyst was found to be effective in the asymmetric
Chem. Eur. J. 2015, 21, 1 – 5
1,6-addition of both d-unsubstituted and d-methyl-substituted dienyl ketones to give excellent regioselectivities (up to 95:5 d.r.) and enantioselectivities (up to > 99 % ee).
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Scandium-Catalyzed Asymmetric 1,6Addition of 3-Substituted Oxindoles to Linear Dienyl Ketones
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![Enantioselective Synthesis of Spirooxindole Enols: Regioselective and Asymmetric [3+2] Cyclization of 3-Isothiocyanato Oxindoles with Dibenzylidene Ketones.](/assets/img/hold.png)
