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Cite this: Chem. Commun., 2014, 50, 8934
A catalytic asymmetric hetero-Diels–Alder reaction of olefinic azlactones and isatins: facile access to chiral spirooxindole dihydropyranones†
Received 21st May 2014, Accepted 20th June 2014
Tai-Ping Gao, Jun-Bing Lin, Xiu-Qin Hu and Peng-Fei Xu*
DOI: 10.1039/c4cc03896g www.rsc.org/chemcomm
A catalytic asymmetric hetero-Diels–Alder (HDA) reaction has been achieved through hydrogen-bond directed c-addition of olefinic azlactones to isatins. This methodology provides an efficient access to spirooxindole dihydropyranones in moderate to good yields and with excellent enantioselectivities.
A vinylogous reaction represents a robust strategy toward direct functionalization at the g-position of a,b-unsaturated systems.1 Over the past decade, with the rapid development of organocatalysis,2 the vinylogous reactivity of various nucleophiles was extensively investigated to produce complex chiral molecules.3 Azlactones (or oxazolones)4 are among the most useful starting materials for the synthesis of a-amino acids and heterocyclic scaffolds,5 many examples have been reported using olefinic azlactones as electronpoor acceptors.6 However, the use of olefinic azlactones as pronucleophilic synthons still remains elusive. Recently, Jørgensen and co-workers reported the first organocatalytic vinylogous addition of olefinic azlactones with enals and 2,4-dienals with unprecedented reactivity patterns via covalent aminocatalysis.7 Despite this progress, the development of new transformation utilizing the vinylogous reactivity of azlactone is still a desirable, yet challenging task. The hetero-Diels–Alder (HDA) reaction of carbonyl compounds is of fundamental importance for the construction of six-membered oxygen-containing heterocycles.8 Therefore, enantioselective HDA reactions using aldehydes as dienophiles are extensively investigated based on metal-based chiral Lewis acid or hydrogen-bond donor catalysts, delivering synthetically important dihydropyran derivatives.9 However, highly enantioselective HDA reactions using ketones as dienophiles are relatively rare.10 Furthermore, for the synthesis of chiral dihydropyranones, most of the asymmetric HDA reactions are largely restricted to the use of specific siloxybutadiene derivatives as dienes, such as Danishefsky’s diene and Brassard’s diene.11 Hence, State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and spectra of compounds 3. CCDC 991736. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc03896g
8934 | Chem. Commun., 2014, 50, 8934--8936
Scheme 1
The reactivity of azlactones in an asymmetric DA reaction.
the development of a concise, atom-economical HDA reaction of ketones with other dienes or dienolates is in high demand. Recently, Feng and co-workers12 reported an elegant chiral bisguanidinecatalysed inverse-electron-demand hetero-Diels–Alder (IEDDA) reaction of azlactones and chalcones with the use of azlactones as dienophiles (Scheme 1). Isatins are bidentate activated ketones and always serve as exceptional electrophiles in asymmetric synthesis of biologically relevant 3-hydroxyoxindole derivatives.13 As part of our continuing efforts to develop novel asymmetric transformations,14 herein we reported a new HDA reaction enabled by g-addition of olefinic azlactones to isatins. The catalytic asymmetric version of this transformation would lead to a chiral spirooxindole dihydropyranone derivative,15 which is a key structural element in a number of natural products and synthetic bioactive molecules.16 To validate our hypothesis, a HDA reaction of isatin 1 and olefinic azlactone 2a was chosen for the preliminary test and initial optimization of the reaction parameters. Indeed, it was found that the desired reaction took place in the presence of cinchona alkaloids A–C, all bearing a bifunctional trans-1,2 amino alcohol moiety, to give spirooxindole dihydropyranones 3a in moderate yields and selectivity, with dihydroquinine giving the best results with respect to yield and enantioselectivity (40% yield, 80% ee, Table 1, entry 3). To improve the reactivity, well-documented bifunctional catalysts D and E were also investigated. Unfortunately, no reaction occurred despite the fact that both catalysts were shown as strong hydrogen-bond donor
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Table 1
ChemComm
Optimization of the reaction conditionsa
Entry
Cat.
R1
Solvent
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d 20e 21f
A B C D E F G H F F F F F F F F F F F F F
H H H H H H H H Bn Me Ph Et Ts Et Et Et Et Et Et Et Et
THF THF THF THF THF THF THF THF THF THF THF THF THF DCM DCE CH3CN Toluene Acetone DCE DCE DCE
37 42 40 Trace Trace 55 36 42 60 28 47 56 n.r. 75 76 85 65 94 82 89 83
49 61 80 n.d. n.d. 84 62 40 40 97 28 99 n.d. 94 99 90 80 84 98 90 98
a Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 2a (0.1 mmol), and catalyst (0.02 mmol) in the indicated solvent (1 mL) at room temperature. b Isolated yield. c Determined by chiral HPLC analysis. d The reaction was carried out at 30 1C. e The reaction was carried out at 50 1C. f 1.2 equiv. of 1 was used.
catalysts for the isatin activation (Table 1, entries 4 and 5). To our delight, further investigation revealed that more rigid chiral tertiary amine F–H were promising catalysts with b-isocupreidine17 (b-ICD) giving the best selectivity (84% ee, entry 6), although the yields were still unsatisfactory (Table 1, entries 6–8). Surprisingly, a significant improvement of enantioselectivity was achieved by changing the N-substituent of isatin (entries 9–13). The ethyl group turned out to be the best N-substituent in terms of yield and ee (56% yield and 99% ee, entry 12). Detailed optimization of the solvents revealed that DCE was the best among THF, DCM, acetonitrile, toluene and acetone (entries 14–18). Better results were obtained when the reaction was performed at 30 1C (entry 19 vs. entries 20 and 14). Slight improvement of yield was also observed when 1.2 equiv. of 1 was used (Table 1, entry 21). With the reaction conditions optimized, the generality of the HDA reaction was investigated with respect to both isatin 1 and olefinic azlactone 2, and the results are given in Table 2. Generally, all of the reactions proceeded smoothly to give the corresponding spirooxindole dihydropyranones 3 in moderate
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Table 2
Substrate scope of the HDA reactiona
Entry
R1
R2
R3
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Allyl Isopropyl
H 5-Br 6-Br 7-Br 5-Me 7-Me 5,7-DiMe 5-Cl 6-Cl 5-F 5-Me 5-Br H H H H H H
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-FC6H4 4-FC6H4 3-BrC6H4 4-FC6H4 4-MeOC6H4 2-Naphthyl Ph Ph
82 75 83 79 69 75 77 75 73 63 82 75 73 88 78 76 77 82
98 99 99 75 99 94 99 95 499 95 499 85 97 94 73 76 99 93
(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l) (3m) (3n) (3o) (3p) (3q) (3r)
a Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 2 (0.1 mmol), and organocatalyst F (20 mol%) in DCE (1 mL) at 30 1C. b Isolated yield. c Determined by chiral HPLC analysis.
to good yields (up to 88%) and with good to excellent enantioselectivities (up to 499%). The results in Table 2 show that azlactones 2 with electron-withdrawing substituents gave better enantioselectivities than those with electron-donating and bulky substituents (Table 2, entries 13 and 14 vs. entries 15 and 16). With regard to isatins, a wide range of substrates were well tolerated and the nature of substituents had only a slight effect on the results (entries 2–12). However, compared with C5 and C6 substituents of isatins, a lower ee value was observed with the C7 substituent (entries 2–4). It was found that an isatin with a dialkyl substituent also worked well (entry 7). To extend the scope of substrates, our further examination focused on the N-substituent of isatin. It was found that isatins with N-allyl and N-isopropyl groups reacted smoothly with azlactones to afford the spirooxindoles in good yields and high enantioselectivities (entries 17 and 18). The absolute configuration of the products was assigned to be (R) by X-ray chromatography analysis of compound 3c (Fig. 1).18 A possible reaction mechanism for the present HDA reaction is illustrated in Scheme 2, although at the current stage a
Fig. 1
X-ray crystal structure of compound 3c.
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7 8 Scheme 2
A possible reaction pathway.
stepwise vinylogous aldol/cyclization cascade cannot be ruled out. Initially, both of the reaction partners are synergistically activated by the bifunctional catalyst F to form the hydrogenbonding complex 4, which then undergoes [4+2] annulations through Si face attack of dienolates to isatins to give intermediate 5. Finally, tautomerization and protonation of intermediate 5 give rise to the desired product 3 and regenerate the catalyst. In summary, we have developed an efficient approach for the construction of chiral spirooxindole dihydropyranones through a HDA reaction of isatins and olefinic azlactones. Vinylogous reactivity of azlactones was readily realized through bifunctional activation of both of the reaction partners, and the desired products were produced generally in good yields and with good to excellent enantioselectivity. Further applications of this chemistry toward novel reaction design and synthesis of complex molecules are currently underway. We are grateful to the NSFC (21032005, 21172097 and 21372105), the National Basic Research Program of China (no. 2010CB833203), the International S&T Cooperation Program of China (2013DFR70580), the National Natural Science Foundation from Gansu Province of China (no. 1204WCGA015), and the ‘‘111’’ program from MOE of P. R. China.
9
10
11
12
13
14
Notes and references 1 (a) R. C. Fuson, Chem. Rev., 1935, 16, 1; (b) G. Casiraghi, L. Battistini, C. Curti, G. Rassu and F. Zanardi, Chem. Rev., 2011, 111, 3076; (c) S. E. Denmark, J. R. Heemstra Jr and G. L. Beutner, Angew. Chem., Int. Ed., 2005, 44, 4682; (d) G. Casiraghi and F. Zanardi, Chem. Rev., 2000, 100, 1929. 2 (a) M. Mahlau and B. List, Angew. Chem., Int. Ed., 2013, 52, 518; (b) K. Brak and E. N. Jacobsen, Angew. Chem., Int. Ed., 2013, 52, 534; (c) A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314; ´n and S. Cabrera, Chem. Soc. Rev., 2013, 42, 774; (d) J. Alema (e) S. Shirakawa and K. Maruoka, Angew. Chem., Int. Ed., 2013, 52, 2. 3 For selected examples, see: (a) H. Ube, N. Shimada and M. Terada, Angew. Chem., Int. Ed., 2010, 49, 1858; (b) G. Bergonzini, S. Vera and P. Melchiorre, Angew. Chem., Int. Ed., 2010, 49, 9685; (c) L. Ratjen, P. Garcı´a-Garcı´a, F. Lay, M. E. Beck and B. List, Angew. Chem., Int. Ed., 2011, 50, 754; (d) C. Curti, G. Rassu, V. Zambrano, L. Pinna, G. Pelosi, A. Sartori, L. Battistini, F. Zanardi and G. Casiraghi, Angew. Chem., Int. Ed., 2012, 51, 6200; (e) D. Uraguchi, K. Yoshioka, Y. Ueki and T. Ooi, J. Am. Chem. Soc., 2012, 134, 19370. 4 (a) A.-N. R. Alba and R. Rios, Chem. – Asian J., 2011, 6, 720; (b) J. S. Fisk, R. A. Mosey and J. J. Tepe, Chem. Soc. Rev., 2007, 36, 1432; (c) R. A. Mosey, J. S. Fisk and J. J. Tepe, Tetrahedron: Asymmetry, 2008, 19, 2755; (d) N. M. Hewlett, C. D. Hupp and J. J. Tepe, Synthesis, 2009, 2825. 5 (a) B. M. Trost and L. C. Czabaniuk, Chem. – Eur. J., 2013, 19, 15210; (b) J. S. Oh, K. Kim II and C. E. Song, Org. Biomol. Chem., 2011,
8936 | Chem. Commun., 2014, 50, 8934--8936
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9, 7983; (c) Y. J. Lee, J. Seo, D. G. Kim, H. Park and B. S. Jeong, Synlett, 2013, 701; (d) P. Finkbeiner, N. M. Weckenmann and B. J. Nachtsheim, Org. Lett., 2014, 16, 1326; (e) S. Peddibhotla and J. J. Tepe, J. Am. Chem. Soc., 2004, 126, 12776; ( f ) R. S. Z. Saleem and J. J. Tepe, J. Org. Chem., 2010, 75, 4330. (a) Z.-C. Geng, N. Li, J. Chen, X.-F. Huang, B. Wu, G.-G. Liu and X.-W. Wang, Chem. Commun., 2012, 48, 4713; (b) L. Tian, G.-Q. Xu, Y.-H. Li, Y.-M. Liang and P.-F. Xu, Chem. Commun., 2014, 50, 2428; (c) M. G. Esguevillas, J. Adrio and J. C. Carretero, Chem. Commun., 2013, 49, 4649; (d) W.-Y. Han, S.-W. Li, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, Chem. – Eur. J., 2013, 19, 5551. L. D. Amico, L. Albrecht, T. Naicker, P. H. Poulsen and K. A. Jørgensen, J. Am. Chem. Soc., 2013, 135, 8063. For reviews, see: (a) K. A. Jørgensen, Angew. Chem., Int. Ed., 2000, 39, 3558; (b) K. C. Nicolaou, S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1668; (c) E. J. Corey, Angew. Chem., Int. Ed., 2002, 41, 1650; For selected examples, see: (d) G. Ujaque, P. S. Lee, K. N. Houk, M. F. Hentemann and S. J. Danishefsky, Chem. – Eur. J., 2002, 8, 3423. (a) Y. Huang, A. K. Unni, A. N. Thadani and V. H. Rawal, Nature, 2003, 424, 146; (b) Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng and G. Zhang, Org. Lett., 2004, 6, 2185; (c) Z. Yu, X. Liu, Z. Dong, M. Xie and X. Feng, Angew. Chem., Int. Ed., 2008, 47, 1308; (d) L. Lin, Y. Kuang, X. Liu and X. Feng, Org. Lett., 2011, 13, 3868; (e) L. Lin, Z. Chen, X. Yang, X. Liu and X. Feng, Org. Lett., 2008, 10, 1311; ( f ) A. K. Unni, N. Takenaka, H. Yamamoto and V. H. Rawal, J. Am. Chem. Soc., 2005, 127, 1336. (a) K. A. Jørgensen, Eur. J. Org. Chem., 2004, 2093; (b) B. Zhao and T.-P. Loh, Org. Lett., 2013, 15, 2914; (c) H.-L. Cui and F. Tanaka, Chem. – Eur. J., 2013, 19, 6213; (d) Y. Huang and V. H. Rawal, J. Am. Chem. Soc., 2002, 124, 9662. (a) S. Danishefsky, T. Kitahara, C. F. Yan and J. Morris, J. Am. Chem. Soc., 1979, 101, 6996; (b) S. J. Danishefsky and M. P. DeNinno, Angew. Chem., Int. Ed., 1987, 26, 15; (c) L. L. Lin, X. H. Liu and M. X. Feng, Synlett, 2007, 2147; (d) J. Savard and P. Brassard, Tetrahedron Lett., 1979, 20, 4911. (a) S. Dong, X. Liu, X. Chen, F. Mei, Y. Zhang, B. Gao, L. Lin and X. Feng, J. Am. Chem. Soc., 2010, 132, 10650; For related examples, see: (b) M. Terada and H. Nii, Chem. – Eur. J., 2011, 17, 1760; (c) Y. Ying, Z. Chai, H. F. Wang, P. Li, C. W. Zheng, G. Zhao and Y. P. Cai, Tetrahedron, 2011, 67, 3337. For recent examples, see: (a) I. Saidalimu, X. Fang, X. P. He, J. Liang, X. Yang and F. Wu, Angew. Chem., Int. Ed., 2013, 52, 5566; (b) B. Zhu, W. Zhang, R. Lee, Z. Han, W. Yang, D. Tan, K. W. Huang and Z. Y. Jiang, Angew. Chem., Int. Ed., 2013, 52, 6666; (c) Y. Ogura, M. Akakura, A. Sakakura and K. Ishihara, Angew. Chem., Int. Ed., 2013, 52, 8299. (a) S. Zhao, J.-B. Lin, Y.-Y. Zhao, Y.-M. Liang and P.-F. Xu, Org. Lett., 2014, 16, 1802; (b) G.-J. Duan, J.-B. Ling, W.-P. Wang, Y.-C. Luo and P.-F. Xu, Chem. Commun., 2013, 49, 4625; (c) L. Tian, X.-Q. Hu, Y.-H. Li and P.-F. Xu, Chem. Commun., 2013, 49, 7213; (d) Z.-X. Jia, Y.-C. Luo, X.-N. Cheng, P.-F. Xu and Y.-C. Gu, J. Org. Chem., 2013, 78, 6488; (e) Y. Su, J.-B. Ling, S. Zhang and P.-F. Xu, J. Org. Chem., 2013, 78, 11053; ( f ) J.-B. Ling, Y. Su, H.-L. Zhu, G.-Y. Wang and P.-F. Xu, Org. Lett., 2012, 14, 1090; ( g) J. B. Ling, W.-P. Wang and P.-F. Xu, ChemCatChem, 2011, 3, 302; (h) Y.-L. Zhao, Y. Wang, J. Cao, Y.-M. Liang and P.-F. Xu, Org. Lett., 2014, 16, 2438. For the synthesis of spirooxindole dihydropyrones via covalent nucleophilic or NHC catalysis, see: (a) L. T. Shen, P. L. Shao and S. Ye, Adv. Synth. Catal., 2011, 353, 1943; (b) C. Yao, Z. Xiao, R. Liu, T. Li, W. Jiao and C. Yu, Chem. – Eur. J., 2013, 19, 456; (c) X. Chen, S. Yang, B. A. Song and Y. R. Chi, Angew. Chem., Int. Ed., 2013, 52, 11134; (d) R. Liu, C. Yu, Z. Xiao, T. Li, X. Wang, Y. Xie and C. Yao, Org. Biomol. Chem., 2014, 12, 1885. (a) D. J. Cheng, Y. Ishihara, B. Tan and C. F. Barbas, III, ACS Catal., 2014, 4, 743; (b) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104; (c) C. Carlo and M. Paolo, Org. Lett., 2012, 14, 5590; (d) X. Xie, C. Peng, G. He, H.-J. Leng, B. Wang, W. Huang and B. Han, Chem. Commun., 2012, 48, 10487; (e) A. K. Franz, P. D. Dreyfuss and S. L. Schreiber, J. Am. Chem. Soc., 2007, 129, 1020; ( f ) M. P. Castaldi, D. M. Troast and J. A. Porco, Jr., Org. Lett., 2009, 11, 3362. (a) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. Hatakeyama, J. Am. Chem. Soc., 1999, 121, 10219; (b) A. Nakano, K. Takahashi, J. Ishihara and S. Hatakeyama, Org. Lett., 2006, 8, 5357. CCDC 991736 see the ESI† for details.
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Cite this: Chem. Commun., 2014, 50, 8934
A catalytic asymmetric hetero-Diels–Alder reaction of olefinic azlactones and isatins: facile access to chiral spirooxindole dihydropyranones†
Received 21st May 2014, Accepted 20th June 2014
Tai-Ping Gao, Jun-Bing Lin, Xiu-Qin Hu and Peng-Fei Xu*
DOI: 10.1039/c4cc03896g www.rsc.org/chemcomm
A catalytic asymmetric hetero-Diels–Alder (HDA) reaction has been achieved through hydrogen-bond directed c-addition of olefinic azlactones to isatins. This methodology provides an efficient access to spirooxindole dihydropyranones in moderate to good yields and with excellent enantioselectivities.
A vinylogous reaction represents a robust strategy toward direct functionalization at the g-position of a,b-unsaturated systems.1 Over the past decade, with the rapid development of organocatalysis,2 the vinylogous reactivity of various nucleophiles was extensively investigated to produce complex chiral molecules.3 Azlactones (or oxazolones)4 are among the most useful starting materials for the synthesis of a-amino acids and heterocyclic scaffolds,5 many examples have been reported using olefinic azlactones as electronpoor acceptors.6 However, the use of olefinic azlactones as pronucleophilic synthons still remains elusive. Recently, Jørgensen and co-workers reported the first organocatalytic vinylogous addition of olefinic azlactones with enals and 2,4-dienals with unprecedented reactivity patterns via covalent aminocatalysis.7 Despite this progress, the development of new transformation utilizing the vinylogous reactivity of azlactone is still a desirable, yet challenging task. The hetero-Diels–Alder (HDA) reaction of carbonyl compounds is of fundamental importance for the construction of six-membered oxygen-containing heterocycles.8 Therefore, enantioselective HDA reactions using aldehydes as dienophiles are extensively investigated based on metal-based chiral Lewis acid or hydrogen-bond donor catalysts, delivering synthetically important dihydropyran derivatives.9 However, highly enantioselective HDA reactions using ketones as dienophiles are relatively rare.10 Furthermore, for the synthesis of chiral dihydropyranones, most of the asymmetric HDA reactions are largely restricted to the use of specific siloxybutadiene derivatives as dienes, such as Danishefsky’s diene and Brassard’s diene.11 Hence, State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and spectra of compounds 3. CCDC 991736. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc03896g
8934 | Chem. Commun., 2014, 50, 8934--8936
Scheme 1
The reactivity of azlactones in an asymmetric DA reaction.
the development of a concise, atom-economical HDA reaction of ketones with other dienes or dienolates is in high demand. Recently, Feng and co-workers12 reported an elegant chiral bisguanidinecatalysed inverse-electron-demand hetero-Diels–Alder (IEDDA) reaction of azlactones and chalcones with the use of azlactones as dienophiles (Scheme 1). Isatins are bidentate activated ketones and always serve as exceptional electrophiles in asymmetric synthesis of biologically relevant 3-hydroxyoxindole derivatives.13 As part of our continuing efforts to develop novel asymmetric transformations,14 herein we reported a new HDA reaction enabled by g-addition of olefinic azlactones to isatins. The catalytic asymmetric version of this transformation would lead to a chiral spirooxindole dihydropyranone derivative,15 which is a key structural element in a number of natural products and synthetic bioactive molecules.16 To validate our hypothesis, a HDA reaction of isatin 1 and olefinic azlactone 2a was chosen for the preliminary test and initial optimization of the reaction parameters. Indeed, it was found that the desired reaction took place in the presence of cinchona alkaloids A–C, all bearing a bifunctional trans-1,2 amino alcohol moiety, to give spirooxindole dihydropyranones 3a in moderate yields and selectivity, with dihydroquinine giving the best results with respect to yield and enantioselectivity (40% yield, 80% ee, Table 1, entry 3). To improve the reactivity, well-documented bifunctional catalysts D and E were also investigated. Unfortunately, no reaction occurred despite the fact that both catalysts were shown as strong hydrogen-bond donor
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Table 1
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Optimization of the reaction conditionsa
Entry
Cat.
R1
Solvent
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d 20e 21f
A B C D E F G H F F F F F F F F F F F F F
H H H H H H H H Bn Me Ph Et Ts Et Et Et Et Et Et Et Et
THF THF THF THF THF THF THF THF THF THF THF THF THF DCM DCE CH3CN Toluene Acetone DCE DCE DCE
37 42 40 Trace Trace 55 36 42 60 28 47 56 n.r. 75 76 85 65 94 82 89 83
49 61 80 n.d. n.d. 84 62 40 40 97 28 99 n.d. 94 99 90 80 84 98 90 98
a Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 2a (0.1 mmol), and catalyst (0.02 mmol) in the indicated solvent (1 mL) at room temperature. b Isolated yield. c Determined by chiral HPLC analysis. d The reaction was carried out at 30 1C. e The reaction was carried out at 50 1C. f 1.2 equiv. of 1 was used.
catalysts for the isatin activation (Table 1, entries 4 and 5). To our delight, further investigation revealed that more rigid chiral tertiary amine F–H were promising catalysts with b-isocupreidine17 (b-ICD) giving the best selectivity (84% ee, entry 6), although the yields were still unsatisfactory (Table 1, entries 6–8). Surprisingly, a significant improvement of enantioselectivity was achieved by changing the N-substituent of isatin (entries 9–13). The ethyl group turned out to be the best N-substituent in terms of yield and ee (56% yield and 99% ee, entry 12). Detailed optimization of the solvents revealed that DCE was the best among THF, DCM, acetonitrile, toluene and acetone (entries 14–18). Better results were obtained when the reaction was performed at 30 1C (entry 19 vs. entries 20 and 14). Slight improvement of yield was also observed when 1.2 equiv. of 1 was used (Table 1, entry 21). With the reaction conditions optimized, the generality of the HDA reaction was investigated with respect to both isatin 1 and olefinic azlactone 2, and the results are given in Table 2. Generally, all of the reactions proceeded smoothly to give the corresponding spirooxindole dihydropyranones 3 in moderate
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Table 2
Substrate scope of the HDA reactiona
Entry
R1
R2
R3
Yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Et Allyl Isopropyl
H 5-Br 6-Br 7-Br 5-Me 7-Me 5,7-DiMe 5-Cl 6-Cl 5-F 5-Me 5-Br H H H H H H
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-FC6H4 4-FC6H4 3-BrC6H4 4-FC6H4 4-MeOC6H4 2-Naphthyl Ph Ph
82 75 83 79 69 75 77 75 73 63 82 75 73 88 78 76 77 82
98 99 99 75 99 94 99 95 499 95 499 85 97 94 73 76 99 93
(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l) (3m) (3n) (3o) (3p) (3q) (3r)
a Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 2 (0.1 mmol), and organocatalyst F (20 mol%) in DCE (1 mL) at 30 1C. b Isolated yield. c Determined by chiral HPLC analysis.
to good yields (up to 88%) and with good to excellent enantioselectivities (up to 499%). The results in Table 2 show that azlactones 2 with electron-withdrawing substituents gave better enantioselectivities than those with electron-donating and bulky substituents (Table 2, entries 13 and 14 vs. entries 15 and 16). With regard to isatins, a wide range of substrates were well tolerated and the nature of substituents had only a slight effect on the results (entries 2–12). However, compared with C5 and C6 substituents of isatins, a lower ee value was observed with the C7 substituent (entries 2–4). It was found that an isatin with a dialkyl substituent also worked well (entry 7). To extend the scope of substrates, our further examination focused on the N-substituent of isatin. It was found that isatins with N-allyl and N-isopropyl groups reacted smoothly with azlactones to afford the spirooxindoles in good yields and high enantioselectivities (entries 17 and 18). The absolute configuration of the products was assigned to be (R) by X-ray chromatography analysis of compound 3c (Fig. 1).18 A possible reaction mechanism for the present HDA reaction is illustrated in Scheme 2, although at the current stage a
Fig. 1
X-ray crystal structure of compound 3c.
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7 8 Scheme 2
A possible reaction pathway.
stepwise vinylogous aldol/cyclization cascade cannot be ruled out. Initially, both of the reaction partners are synergistically activated by the bifunctional catalyst F to form the hydrogenbonding complex 4, which then undergoes [4+2] annulations through Si face attack of dienolates to isatins to give intermediate 5. Finally, tautomerization and protonation of intermediate 5 give rise to the desired product 3 and regenerate the catalyst. In summary, we have developed an efficient approach for the construction of chiral spirooxindole dihydropyranones through a HDA reaction of isatins and olefinic azlactones. Vinylogous reactivity of azlactones was readily realized through bifunctional activation of both of the reaction partners, and the desired products were produced generally in good yields and with good to excellent enantioselectivity. Further applications of this chemistry toward novel reaction design and synthesis of complex molecules are currently underway. We are grateful to the NSFC (21032005, 21172097 and 21372105), the National Basic Research Program of China (no. 2010CB833203), the International S&T Cooperation Program of China (2013DFR70580), the National Natural Science Foundation from Gansu Province of China (no. 1204WCGA015), and the ‘‘111’’ program from MOE of P. R. China.
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