ChemComm View Article Online
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 14601 Received 7th July 2014, Accepted 25th September 2014 DOI: 10.1039/c4cc05207b
View Journal | View Issue
An organocatalytic domino Michael-alkylation reaction: highly enantioselective construction of spiro-cyclopentanoneoxindoles and tetronic acid scaffolds† Jing Zhou,ab Qi-Lin Wang,ab Lin Peng,a Fang Tian,a Xiao-Ying Xu*a and Li-Xin Wang*a
www.rsc.org/chemcomm
A new organocatalytic asymmetric domino Michael-alkylation reaction of methyleneindolinones and c-halogenated-b-ketoesters is described. A variety of spiro-cyclopentanoneoxindoles were obtained in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to 499% ee) via a-alkylation. Interestingly, O-alkylated products with tetronic acid motifs could be obtained by tuning the N-protecting groups on methyleneindolinones with excellent enantioselectivities (up to 499% ee).
Optically active spirocyclic oxindoles are core structural motifs in many natural products and biologically active molecules.1 In particular, chiral spiro-cyclopentaneoxindole scaffolds constitute important structural motifs in biologically relevant compounds such as natural products and pharmaceuticals.2 As a result, many efficient strategies have been developed including [3+2] cycloaddition of methyleneindolinones with allenoates3 or MBH carbonates4 and domino reactions such as Michael-aldol,5 Michael–Henry6 and double Michael additions.7 However, the reported methods mainly focused on the preparation of spirocyclopentane6,7a,8 or cyclopentene oxindoles,3,4,9 and asymmetric protocols to construct spirooxindoles with cyclopentanone motifs were less exploited. Therefore, development of more new efficient methods to access versatile and structural spirocyclopentaneoxindoles is useful and desirable. Currently, our group is endeavoring to develop new protocols to construct spirooxindoles with novel structures, especially by [3+2] annulation of isocyanoesters with methyleneindolinones. Based on our continuing interest in the construction of more complex and novel spirocyclic oxindoles,10 we envisioned that the asymmetric reaction of methyleneindolinones with g-halogenated-b-ketoesters
could be catalyzed by chiral thioureas or squaramides to afford spiro-cyclopentanoneoxindoles via a domino Michael/a-alkylation reaction. g-Halogenated-b-ketoesters are commercially available and extensively used in asymmetric catalysis.11 In 2006, Jørgensen reported the first organocatalytic domino Michael-aldol/cyclization reaction of 4-chloro-3-oxobutanoates with a,b-unsaturated aldehydes.11a Since then, several asymmetric protocols have been developed, such as asymmetric Michael/a-alkylation of aldehydes,11b asymmetric domino Mannich-cyclization of imines,11c asymmetric Michael–alkylation of nitroalkenes.11d,e To the best of our knowledge, the reaction of g-halogenated-b-ketoesters with methyleneindolinones has not been documented. Herein, we wish to report the first domino Michael/a-alkylation reaction of methyleneindolinones with g-halogenated-b-ketoesters to access spirocyclopentanoneoxindoles. Interestingly, tuning the N-protecting groups on alkylidene oxindoles via an O-alkylation process led to 3-substituted oxindoles with tetronic acid motifs which are also important and versatile building blocks in organic synthesis (Scheme 1).12 To validate our hypothesis, N-Boc and N-methyl protected methyleneindolinones 1a and 1b were selected to react with ethyl 4-chloro-acetoacetate 2a in the presence of bifunctional thiourea– tertiary amine catalyst 3a with KHCO3 in chloroform at room temperature (Table 1, entries 1 and 2).13 To our delight, N-Boc protected methyleneindolinone 1a afforded spiro-cyclopentanoneoxindole 4a as the major product (Table 1, entry 1), while N-methyl protected methyleneindolinone 1b gave O-alkylated
a
Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China. E-mail: [email protected], [email protected] b University of Chinese Academy of Sciences, Beijing 10049, China † Electronic supplementary information (ESI) available: Experimental procedures, spectral data of new compounds, and crystallographic data. CCDC 999669 and 1000582. For the ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc05207b
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Asymmetric domino Michael-alkylation reaction.
Chem. Commun., 2014, 50, 14601--14604 | 14601
View Article Online
Communication
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Table 1
ChemComm
Optimization of the reaction conditionsa
Table 2 Scope of the reaction of N-Boc protected methyleneindolinones with g-halogenated-b-ketoestersa
Entry Cat. 1/R Solvent
T (1C) x
Yieldb (%) drc
eed (%)
1 2e 3 4 5 6 7 8 9 10 11 12 13 f 14 f 15 f 16 f 17 f
25 25 25 25 25 25 25 25 25 25 25 25 5 30 30 30 30
69 70 60 64 54 49 78 51 82 95 86 88 96 95 97 94 66
90/94 51g/49 g 82/73 87h/88h 77h/40h 75h/65h 499/96 499/92 83/75 81/75 79/59 57/40 89 499 499 499 84
3a 3a 3b 3c 3d 3e 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a
1a 1b 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 n-Hexane PhCH3 THF EtOAc CH3CN THF THF THF THF THF
20 20 20 20 20 20 20 20 20 20 20 20 20 20 10 5 1
4a/1.8 : 1 5a/1.0 : 1 4a/3.5 : 1 4a/1.5 : 1 4a/1.5 : 1 4a/2.0 : 1 4a/1.8 : 1 4a/1.5 : 1 4a/1.9 : 1 4a/4.3 : 1 4a/4.6 : 1 4a/1.3 : 1 4a/4.6 : 1 4a/7.3 : 1 4a/6.7 : 1 4a/7.3 : 1 4a/6.1 : 1
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL solvent. b Isolated yields of mixtures of diastereomers. c Determined by chiral HPLC analysis. d The major diastereomers, determined by chiral HPLC analysis. e The second step was performed for 48 h. f The first step was performed for 48 h. g Contrary configuration to 5f. h Contrary configuration to 4d.
product 5a (Table 1, entry 2). Firstly, N-Boc protected methyleneindolinone 1a was selected as the model substrate to optimize the reaction conditions. A series of tertiary-amine based catalysts (Fig. 1) were investigated, and the results revealed that 3a could promote the process more efficiently in terms of stereoselectivity (Table 1, entries 1 vs. 3–6). Then an array of solvents were examined. Various solvents were well tolerated, and THF was identified as the most suitable solvent in terms of yield and stereoselectivity (Table 1, entry 10). Moreover, reaction temperature and catalyst loadings were also studied. Further improvement was achieved by lowering the reaction temperature, and the optically pure (499% ee) product was obtained at 30 1C (Table 1, entry 14). Notably, the presence of 5 mol% 3a was sufficient to afford the desired product in excellent yield and enantioselectivity (94% yield, 499% ee, Table 1, entry 16). Upon further lowering the catalyst loading to 1 mol%, the reaction
Fig. 1
Screened catalysts.
14602 | Chem. Commun., 2014, 50, 14601--14604
Entry 1/R1, R2 1 2 3 4e 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1a/C6H4CO, H 1c/4-FC6H4CO, H 1d/4-ClC6H4CO, H 1e/4-BrC6H4CO, H 1f/4-MeC6H4CO, H 1g/4-MeOC6H4CO, H 1h/2-MeC6H4CO, H 1i/3-MeOC6H4CO, H 1j/2-naphthylCO, H 1k/C6H4CO, 5-F 1l/C6H4CO, 5-Br 1m/C6H4CO, 5-Me 1n/CH3CO, H 1o/CO2Me,H 1p/CO2Et, H 1q/CO2tBu, H 1r/CO2Bn, H 1a/C6H4CO, H 1a/C6H4CO, H 1s/Ph, H 1t/n-Pr, H
2/R3, R4
Yieldb (%) drc
2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2b/Cl, Me 2c/Br, Me 2a/Cl, Et 2a/Cl, Et
4a/94 4b/92 4c/95 4d/93 4e/96 4f/92 4g/93 4h/92 4i/92 4j/92 4k/90 4l/88 4m/80 4n/93 4o/95 4p/90 4q/91 4r/94 4r/90 4s/84 4t/92
eed (%)
7.3 : 1 499 8.1 : 1 96 10.2 : 1 90 7.7 : 1 82 7.2 : 1 91 12.1 : 1 92 3.6 : 1 84 12.2 : 1 499 10.1 : 1 90 7.0 : 1 89 2.0 : 1 55 2.0 : 1 66 1.3 : 1 63 1.9 : 1 96 1.6 : 1 79 1.9 : 1 90 1.4 : 1 81 6.3 : 1 92 4.3 : 1 47 2.7 : 1 36 1.3 : 1 16
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL THF. b Isolated yields of mixtures of diastereomers. c Determined by 1H NMR. d The major diastereomers, determined by chiral HPLC analysis. e The absolute configuration of 4d was determined to be (C8S, C9S, C22S) by X-ray crystallography (see ESI).
also could still work, and acceptable yield and stereoselectivity were obtained (Table 1, entry 17). Based on these screenings, a set of optimal reaction conditions were established: 0.2 mmol 1a, 0.2 mmol 2a and catalyst 3a (5 mol%) were stirred in THF (1.0 mL) for 48 h at 30 1C, then 2 equiv. of KHCO3 was added and the crude mixture was stirred for 24 h at room temperature. Under the optimal reaction conditions, the generality of this protocol was studied. Firstly, a wide range of methyleneindolinones were studied (Table 2). The electronic features and positions of substituents on the benzoyl substituents of methyleneindolinones delivered no significant influences on the yields and enantioselectivities, and all the cases afforded excellent yields and good to excellent enantioselectivities (92–96% yield and 82–499% ee; Table 2, entries 1–8). The positions of the substituents only affected the diastereoselectivities and the ortho-substituted substrate afforded a lower dr value than the corresponding meta- and para-substituted counterparts (Table 2, entries 7 vs. 2–6 and 8). The optimal protocol was also expanded to the transformations of naphthyl substituted methyleneindolinone 1j and 5-fluorosubstituted methyleneindolinone 1k with ethyl 4-chloroacetoacetate 2a, and good results were obtained (Table 2, entries 9 and 10), while 5-bromo-substituted, 5-methyl-substituted and acetyl substituted methyleneindolinones provided good yields but moderate enantioselectivities (Table 2, entries 11–13). Introduction of ester substituents on methyleneindolinones slightly affected the enantioselectivities, but obviously decreased the diastereoselectivities
This journal is © The Royal Society of Chemistry 2014
View Article Online
ChemComm
Communication
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Table 3 Scope of N-alkyl protected methyleneindolinones and ethyl 4-chloroacetoacetate 2aa
Entry
1/R1, R2
Yieldb (%)
drc
eed (%)
1 2 3 4 5 6e
1b/Me, COC6H5 1u/Et, COC6H5 1v/Bn, COC6H5 1w/Me, COCH3 1x/Me, CO2Et 1y/Me, 4-ClC6H4CO
72 70 78 75 73 68
5a/1.2 : 1 5b/1.1 : 1 5c/19.0 : 1 5d/1.6 : 1 5e/1.2 : 1 5f/1.5 : 1
84/499 96/94 99/94 91/89 499/499 499/96
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL CHCl3. b Isolated yields of mixtures of diastereomers. c Determined by chiral HPLC analysis. d The major diastereomers, determined by chiral HPLC analysis. e The absolute configuration of 5f was determined to be (C8S, C9S) by X-ray crystallography (see ESI).
(Table 2, entries 14–17). In addition, methyl 4-chloroacetoacetate and methyl 4-bromoacetoacetate were also tested. Methyl 4-chloroacetoacetate afforded results comparable with those of ethyl 4-chloroacetoacetate (Table 2, entry 18 vs. entry 1), while methyl 4-bromoacetoacetate afforded comparable yield but poor enantioselectivity (Table 2, entry 19 vs. entry 1). Moreover, Ph and n-Pr substituted methyleneindolinones provided good yields but poor enantioselectivities (Table 2, entries 20 and 21). The reaction of N-methyl protected methyleneindolinone 1b with ethyl 4-chloroacetoacetate 2a afforded an O-alkylated product with a tetronic acid scaffold. This interesting result inspired us to further optimize the conditions of this transformation (see ESI†). Under the optimal reaction conditions, a variety of N-alkyl protected methyleneindolinones were evaluated. They all provided O-alkylated products 5 as the main products and the results are described in Table 3. All the cases afforded good yields and good to excellent enantioselectivities. Notably, N-benzyl methyleneindolinones gave excellent enantioselectivity (99% ee) and diastereoselectivity (19.0 : 1) (Table 3, entry 3). However, other substrates gave poor diastereoselectivities (Table 3, entries 1, 2 and 4–6). Ester substituted methyleneindolinone 1x also afforded excellent enantioselectivity (499% ee) but poor diastereoselectivity (1.2 : 1) (Table 3, entry 5). To evaluate the different chemoselectivities obtained through the protecting group, we investigated a model reaction: 0.1 mmol of 1a, 0.1 mmol of 1b, 0.1 mmol of 2a and catalyst 3a (20 mol%) were stirred in CHCl3 (1.0 mL) for 24 h at room temperature, then 2 equiv. of KHCO3 was added and the crude mixture was stirred for 24 h at room temperature (Scheme 2). Only product 4a was observed, and 5a was not obtained.
Scheme 2
Competitive reaction.
This journal is © The Royal Society of Chemistry 2014
Scheme 3
Plausible mechanism for chemoselectivities.
Based on the experiment results, a plausible mechanism is proposed in Scheme 3. The tertiary amine groups of thiourea– tertiary amine catalysts activate 4-chloroacetoacetate in its enol form and the thiourea moieties activate methyleneindolinones through hydrogen bonding via a transition state (TS) (Scheme 3). Through the dual activation of a thiourea–tertiary amine catalyst, the Michael reaction was realized and generated intermediary Michael adducts A (4a0 and 5a0 ). Different chemoselectivities may be determined by different acidities of the benzylic positions of 4a0 and 5a0 , which led to different reactivities of 4a0 and 5a0 . When the substituent on the nitrogen atom of the oxindole is Boc, the electron withdrawing feature of the group makes the C-3 of the oxindole more acidic and preferable to form enolate ion 4ab in the presence of KHCO3. Enolate ion 4ab was further transformed to spiro-cyclopentanoneoxindole 4a via a-alkylation, while N-methyl protected methyleneindolinone is more preferable to form enolate ion 5ab due to its electron donating feature and gave a 3-substituted oxindole with a tetronic acid motif 5a via O-alkylation. In summary, we have developed a new organocatalyzed enantioselective Michael-alkylation domino reaction of methyleneindolinones with g-halogenated-b-ketoesters. Different main products were obtained by tuning the N-protecting groups on methyleneindolinones. N-Boc protected methyleneindolinones afforded a variety of spiro-cyclopentanoneoxindoles in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to 499% ee), while N-alkyl protected ones gave O-alkylated products with tetronic acid scaffolds in excellent enantioselectivities (up to 499% ee). This protocol provides a new method to access spiro-cyclopentanoneoxindoles and 3-substituted oxindoles with tetronic acid motifs. This work was supported by the National Natural Science Foundation of China (No. 21272230) and the Western Light Talent Culture Project.
Notes and references 1 Selected examples: (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) S. S. Girija and Y. D. Zelalem, Chem. Rev., 2012, 112, 6104; (c) R. B. Nicolas, J. B. Joseph and K. F. Annaliese, Org. Biomol. Chem., 2012, 10, 5165; (d) L. Hong and R. Wang, Adv. Synth. Catal., 2013, 355, 1023; (e) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao and L.-Z. Gong, J. Am. Chem. Soc., 2009, 131, 13819; ( f ) Y. Liu, M. Nappi, E. Arceo, S. Vera and P. Melchiorre, J. Am. Chem. Soc., 2011, 133, 15212; (g) Y.-Y. Han, W.-B. Chen, W.-Y. Han, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2012, 14, 490; (h) X.-L. Liu, W.-Y. Han, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2013, 15, 1246; (i) D.-J. Cheng, Y. Ishihara, B. Tan and C. F. Barbas III, ACS Catal., 2014, 4, 743.
Chem. Commun., 2014, 50, 14601--14604 | 14603
View Article Online
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Communication 2 Selected examples: (a) B. M. Trost, N. A. Cramer and S. M. Silverman, J. Am. Chem. Soc., 2007, 129, 12396; (b) X. Li, Y.-M. Li, F. Z. Peng, S.-T. Wu, Z.-Q. Li, Z.-W. Sun, H.-B. Zhang and Z.-H. Shao, Org. Lett., 2011, 13, 6160. 3 Selected example: A. Voituriez, N. Pinto, M. Neel, P. Retailleau and A. Marinetti, Chem. – Eur. J., 2010, 16, 12541. 4 Selected examples: (a) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133, 4672; (b) F. Zhong, X. Han, Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837. 5 Selected examples: (a) B. N. Tan, R. Candeias and C. F. Barbas III, Nat. Chem., 2011, 3, 473; (b) K. Albertshofer, K. E. Anderson and C. F. Barbas III, Org. Lett., 2012, 14, 5968; (c) A. Noole, K. Ilmarinen, ¨rving, M. Lopp and T. Kanger, J. Org. Chem., 2013, 78, 8117. I. Ja 6 Selected example: K. Albertshofer, B. Tan and C. F. Barbas III, Org. Lett., 2012, 14, 1834. 7 Selected examples: (a) Y. M. Li, X. Li, F. Z. Peng, Z. Q. Li, S. T. Wu, Z. W. Sun, H. B. Zhang and Z. H. Shao, Org. Lett., 2011, 13, 6200; (b) B. Zhou, Z. Luo and Y. C. Li, Chem. – Eur. J., 2013, 19, 4428. 8 Selected examples: (a) S. L. Zhang, H. X. Xie, J. Zhu, H. Li, X. S. Zhang, J. Li and W. Wang, Nat. Commun., 2011, 2, 211; (b) W. Sun, G. Zhu, C. Wu, L. Hong and R. Wang, Chem. – Eur. J., 2012, 18, 6737; (c) K. Jiang, B. Tiwari and Y. R. Chi, Org. Lett., 2012, 14, 2382. 9 Selected examples: (a) J. Peng, X. Huang, L. Jiang, H. L. Cui and Y. C. Chen, Org. Lett., 2011, 13, 4584; (b) W. Sun, G. Zhu, L. Hong and R. Wang, Chem. – Eur. J., 2012, 18, 13959.
14604 | Chem. Commun., 2014, 50, 14601--14604
ChemComm 10 (a) L. L. Wang, L. Peng, J. F. Bai, Q. C. Huang, X. Y. Xu and L. X. Wang, Chem. Commun., 2010, 46, 8064; (b) L. L. Wang, L. Peng, J. F. Bai, L. N. Jia, X. Y. Luo, Q. C. Huang, X. Y. Xu and L. X. Wang, Chem. Commun., 2011, 47, 5593; (c) L. L. Wang, J. F. Bai, L. Peng, L. W. Qi, L. N. Jia, Y. L. Guo, X. Y. Luo, X. Y. Xu and L. X. Wang, Chem. Commun., 2012, 48, 5175; (d) Q. L. Wang, L. Peng, F. Y. Wang, M. L. Zhang, L. N. Jia, F. Tian, X. Y. Xu and L. X. Wang, Chem. Commun., 2013, 49, 9422. 11 Selected examples: (a) M. Marigo, S. Bertelsen, A. Landa and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 5475; (b) R. Rios, J. Vesely, ´n, I. Ibrahem, G. L. Zhao and A. Co ´rdova, Tetrahedron Lett., H. Sunde 2007, 48, 5835; (c) N. H. Luo, X. Sun, Y. Y. Yan, S. Z. Nie and M. Yan, Tetrahedron: Asymmetry, 2011, 22, 1536; (d) X. W. Dou, X. Y. Han and Y. X. Lu, Chem. – Eur. J., 2012, 18, 85; (e) Y. Y. Yan, R. J. Lu, J. J. Wang, Y. N. Xuan and M. Yan, Tetrahedron, 2012, 68, 6123; ( f ) H. M. Ma, L. L. Yang, Y. Ni, J. Zhang, C. X. Li, G. W. Zheng, H. Y. Yang and J. H. Xu, Adv. Synth. Catal., 2012, 354, 1765. 12 Selected examples: (a) Y. L. Li, H. Chen, C. L. Shi, D. Q. Shi and S. J. Ji, J. Comb. Chem., 2010, 12, 231; (b) M. Dabiri, Z. N. Tisseh, M. Bahramnejad and A. Bazgir, Ultrason. Sonochem., 2011, 18, 1153; (c) M. Vilches-Herrera, A. Spannenberg, P. Langer and V. O. Iaroshenko, Tetrahedron, 2013, 69, 5955; (d) Q. Wu, H. Feng, D. D. Guo, M. S. Yi, X. H. Wang, B. Jiang and S. J. Tu, J. Heterocycl. Chem., 2013, 50, 599. 13 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672; (b) T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2006, 128, 9413.
This journal is © The Royal Society of Chemistry 2014
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 14601 Received 7th July 2014, Accepted 25th September 2014 DOI: 10.1039/c4cc05207b
View Journal | View Issue
An organocatalytic domino Michael-alkylation reaction: highly enantioselective construction of spiro-cyclopentanoneoxindoles and tetronic acid scaffolds† Jing Zhou,ab Qi-Lin Wang,ab Lin Peng,a Fang Tian,a Xiao-Ying Xu*a and Li-Xin Wang*a
www.rsc.org/chemcomm
A new organocatalytic asymmetric domino Michael-alkylation reaction of methyleneindolinones and c-halogenated-b-ketoesters is described. A variety of spiro-cyclopentanoneoxindoles were obtained in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to 499% ee) via a-alkylation. Interestingly, O-alkylated products with tetronic acid motifs could be obtained by tuning the N-protecting groups on methyleneindolinones with excellent enantioselectivities (up to 499% ee).
Optically active spirocyclic oxindoles are core structural motifs in many natural products and biologically active molecules.1 In particular, chiral spiro-cyclopentaneoxindole scaffolds constitute important structural motifs in biologically relevant compounds such as natural products and pharmaceuticals.2 As a result, many efficient strategies have been developed including [3+2] cycloaddition of methyleneindolinones with allenoates3 or MBH carbonates4 and domino reactions such as Michael-aldol,5 Michael–Henry6 and double Michael additions.7 However, the reported methods mainly focused on the preparation of spirocyclopentane6,7a,8 or cyclopentene oxindoles,3,4,9 and asymmetric protocols to construct spirooxindoles with cyclopentanone motifs were less exploited. Therefore, development of more new efficient methods to access versatile and structural spirocyclopentaneoxindoles is useful and desirable. Currently, our group is endeavoring to develop new protocols to construct spirooxindoles with novel structures, especially by [3+2] annulation of isocyanoesters with methyleneindolinones. Based on our continuing interest in the construction of more complex and novel spirocyclic oxindoles,10 we envisioned that the asymmetric reaction of methyleneindolinones with g-halogenated-b-ketoesters
could be catalyzed by chiral thioureas or squaramides to afford spiro-cyclopentanoneoxindoles via a domino Michael/a-alkylation reaction. g-Halogenated-b-ketoesters are commercially available and extensively used in asymmetric catalysis.11 In 2006, Jørgensen reported the first organocatalytic domino Michael-aldol/cyclization reaction of 4-chloro-3-oxobutanoates with a,b-unsaturated aldehydes.11a Since then, several asymmetric protocols have been developed, such as asymmetric Michael/a-alkylation of aldehydes,11b asymmetric domino Mannich-cyclization of imines,11c asymmetric Michael–alkylation of nitroalkenes.11d,e To the best of our knowledge, the reaction of g-halogenated-b-ketoesters with methyleneindolinones has not been documented. Herein, we wish to report the first domino Michael/a-alkylation reaction of methyleneindolinones with g-halogenated-b-ketoesters to access spirocyclopentanoneoxindoles. Interestingly, tuning the N-protecting groups on alkylidene oxindoles via an O-alkylation process led to 3-substituted oxindoles with tetronic acid motifs which are also important and versatile building blocks in organic synthesis (Scheme 1).12 To validate our hypothesis, N-Boc and N-methyl protected methyleneindolinones 1a and 1b were selected to react with ethyl 4-chloro-acetoacetate 2a in the presence of bifunctional thiourea– tertiary amine catalyst 3a with KHCO3 in chloroform at room temperature (Table 1, entries 1 and 2).13 To our delight, N-Boc protected methyleneindolinone 1a afforded spiro-cyclopentanoneoxindole 4a as the major product (Table 1, entry 1), while N-methyl protected methyleneindolinone 1b gave O-alkylated
a
Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China. E-mail: [email protected], [email protected] b University of Chinese Academy of Sciences, Beijing 10049, China † Electronic supplementary information (ESI) available: Experimental procedures, spectral data of new compounds, and crystallographic data. CCDC 999669 and 1000582. For the ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc05207b
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Asymmetric domino Michael-alkylation reaction.
Chem. Commun., 2014, 50, 14601--14604 | 14601
View Article Online
Communication
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Table 1
ChemComm
Optimization of the reaction conditionsa
Table 2 Scope of the reaction of N-Boc protected methyleneindolinones with g-halogenated-b-ketoestersa
Entry Cat. 1/R Solvent
T (1C) x
Yieldb (%) drc
eed (%)
1 2e 3 4 5 6 7 8 9 10 11 12 13 f 14 f 15 f 16 f 17 f
25 25 25 25 25 25 25 25 25 25 25 25 5 30 30 30 30
69 70 60 64 54 49 78 51 82 95 86 88 96 95 97 94 66
90/94 51g/49 g 82/73 87h/88h 77h/40h 75h/65h 499/96 499/92 83/75 81/75 79/59 57/40 89 499 499 499 84
3a 3a 3b 3c 3d 3e 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a 3a
1a 1b 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 n-Hexane PhCH3 THF EtOAc CH3CN THF THF THF THF THF
20 20 20 20 20 20 20 20 20 20 20 20 20 20 10 5 1
4a/1.8 : 1 5a/1.0 : 1 4a/3.5 : 1 4a/1.5 : 1 4a/1.5 : 1 4a/2.0 : 1 4a/1.8 : 1 4a/1.5 : 1 4a/1.9 : 1 4a/4.3 : 1 4a/4.6 : 1 4a/1.3 : 1 4a/4.6 : 1 4a/7.3 : 1 4a/6.7 : 1 4a/7.3 : 1 4a/6.1 : 1
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL solvent. b Isolated yields of mixtures of diastereomers. c Determined by chiral HPLC analysis. d The major diastereomers, determined by chiral HPLC analysis. e The second step was performed for 48 h. f The first step was performed for 48 h. g Contrary configuration to 5f. h Contrary configuration to 4d.
product 5a (Table 1, entry 2). Firstly, N-Boc protected methyleneindolinone 1a was selected as the model substrate to optimize the reaction conditions. A series of tertiary-amine based catalysts (Fig. 1) were investigated, and the results revealed that 3a could promote the process more efficiently in terms of stereoselectivity (Table 1, entries 1 vs. 3–6). Then an array of solvents were examined. Various solvents were well tolerated, and THF was identified as the most suitable solvent in terms of yield and stereoselectivity (Table 1, entry 10). Moreover, reaction temperature and catalyst loadings were also studied. Further improvement was achieved by lowering the reaction temperature, and the optically pure (499% ee) product was obtained at 30 1C (Table 1, entry 14). Notably, the presence of 5 mol% 3a was sufficient to afford the desired product in excellent yield and enantioselectivity (94% yield, 499% ee, Table 1, entry 16). Upon further lowering the catalyst loading to 1 mol%, the reaction
Fig. 1
Screened catalysts.
14602 | Chem. Commun., 2014, 50, 14601--14604
Entry 1/R1, R2 1 2 3 4e 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1a/C6H4CO, H 1c/4-FC6H4CO, H 1d/4-ClC6H4CO, H 1e/4-BrC6H4CO, H 1f/4-MeC6H4CO, H 1g/4-MeOC6H4CO, H 1h/2-MeC6H4CO, H 1i/3-MeOC6H4CO, H 1j/2-naphthylCO, H 1k/C6H4CO, 5-F 1l/C6H4CO, 5-Br 1m/C6H4CO, 5-Me 1n/CH3CO, H 1o/CO2Me,H 1p/CO2Et, H 1q/CO2tBu, H 1r/CO2Bn, H 1a/C6H4CO, H 1a/C6H4CO, H 1s/Ph, H 1t/n-Pr, H
2/R3, R4
Yieldb (%) drc
2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2a/Cl, Et 2b/Cl, Me 2c/Br, Me 2a/Cl, Et 2a/Cl, Et
4a/94 4b/92 4c/95 4d/93 4e/96 4f/92 4g/93 4h/92 4i/92 4j/92 4k/90 4l/88 4m/80 4n/93 4o/95 4p/90 4q/91 4r/94 4r/90 4s/84 4t/92
eed (%)
7.3 : 1 499 8.1 : 1 96 10.2 : 1 90 7.7 : 1 82 7.2 : 1 91 12.1 : 1 92 3.6 : 1 84 12.2 : 1 499 10.1 : 1 90 7.0 : 1 89 2.0 : 1 55 2.0 : 1 66 1.3 : 1 63 1.9 : 1 96 1.6 : 1 79 1.9 : 1 90 1.4 : 1 81 6.3 : 1 92 4.3 : 1 47 2.7 : 1 36 1.3 : 1 16
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL THF. b Isolated yields of mixtures of diastereomers. c Determined by 1H NMR. d The major diastereomers, determined by chiral HPLC analysis. e The absolute configuration of 4d was determined to be (C8S, C9S, C22S) by X-ray crystallography (see ESI).
also could still work, and acceptable yield and stereoselectivity were obtained (Table 1, entry 17). Based on these screenings, a set of optimal reaction conditions were established: 0.2 mmol 1a, 0.2 mmol 2a and catalyst 3a (5 mol%) were stirred in THF (1.0 mL) for 48 h at 30 1C, then 2 equiv. of KHCO3 was added and the crude mixture was stirred for 24 h at room temperature. Under the optimal reaction conditions, the generality of this protocol was studied. Firstly, a wide range of methyleneindolinones were studied (Table 2). The electronic features and positions of substituents on the benzoyl substituents of methyleneindolinones delivered no significant influences on the yields and enantioselectivities, and all the cases afforded excellent yields and good to excellent enantioselectivities (92–96% yield and 82–499% ee; Table 2, entries 1–8). The positions of the substituents only affected the diastereoselectivities and the ortho-substituted substrate afforded a lower dr value than the corresponding meta- and para-substituted counterparts (Table 2, entries 7 vs. 2–6 and 8). The optimal protocol was also expanded to the transformations of naphthyl substituted methyleneindolinone 1j and 5-fluorosubstituted methyleneindolinone 1k with ethyl 4-chloroacetoacetate 2a, and good results were obtained (Table 2, entries 9 and 10), while 5-bromo-substituted, 5-methyl-substituted and acetyl substituted methyleneindolinones provided good yields but moderate enantioselectivities (Table 2, entries 11–13). Introduction of ester substituents on methyleneindolinones slightly affected the enantioselectivities, but obviously decreased the diastereoselectivities
This journal is © The Royal Society of Chemistry 2014
View Article Online
ChemComm
Communication
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Table 3 Scope of N-alkyl protected methyleneindolinones and ethyl 4-chloroacetoacetate 2aa
Entry
1/R1, R2
Yieldb (%)
drc
eed (%)
1 2 3 4 5 6e
1b/Me, COC6H5 1u/Et, COC6H5 1v/Bn, COC6H5 1w/Me, COCH3 1x/Me, CO2Et 1y/Me, 4-ClC6H4CO
72 70 78 75 73 68
5a/1.2 : 1 5b/1.1 : 1 5c/19.0 : 1 5d/1.6 : 1 5e/1.2 : 1 5f/1.5 : 1
84/499 96/94 99/94 91/89 499/499 499/96
a
Unless otherwise noted, the reaction was performed on a 0.2 mmol scale in 1.0 mL CHCl3. b Isolated yields of mixtures of diastereomers. c Determined by chiral HPLC analysis. d The major diastereomers, determined by chiral HPLC analysis. e The absolute configuration of 5f was determined to be (C8S, C9S) by X-ray crystallography (see ESI).
(Table 2, entries 14–17). In addition, methyl 4-chloroacetoacetate and methyl 4-bromoacetoacetate were also tested. Methyl 4-chloroacetoacetate afforded results comparable with those of ethyl 4-chloroacetoacetate (Table 2, entry 18 vs. entry 1), while methyl 4-bromoacetoacetate afforded comparable yield but poor enantioselectivity (Table 2, entry 19 vs. entry 1). Moreover, Ph and n-Pr substituted methyleneindolinones provided good yields but poor enantioselectivities (Table 2, entries 20 and 21). The reaction of N-methyl protected methyleneindolinone 1b with ethyl 4-chloroacetoacetate 2a afforded an O-alkylated product with a tetronic acid scaffold. This interesting result inspired us to further optimize the conditions of this transformation (see ESI†). Under the optimal reaction conditions, a variety of N-alkyl protected methyleneindolinones were evaluated. They all provided O-alkylated products 5 as the main products and the results are described in Table 3. All the cases afforded good yields and good to excellent enantioselectivities. Notably, N-benzyl methyleneindolinones gave excellent enantioselectivity (99% ee) and diastereoselectivity (19.0 : 1) (Table 3, entry 3). However, other substrates gave poor diastereoselectivities (Table 3, entries 1, 2 and 4–6). Ester substituted methyleneindolinone 1x also afforded excellent enantioselectivity (499% ee) but poor diastereoselectivity (1.2 : 1) (Table 3, entry 5). To evaluate the different chemoselectivities obtained through the protecting group, we investigated a model reaction: 0.1 mmol of 1a, 0.1 mmol of 1b, 0.1 mmol of 2a and catalyst 3a (20 mol%) were stirred in CHCl3 (1.0 mL) for 24 h at room temperature, then 2 equiv. of KHCO3 was added and the crude mixture was stirred for 24 h at room temperature (Scheme 2). Only product 4a was observed, and 5a was not obtained.
Scheme 2
Competitive reaction.
This journal is © The Royal Society of Chemistry 2014
Scheme 3
Plausible mechanism for chemoselectivities.
Based on the experiment results, a plausible mechanism is proposed in Scheme 3. The tertiary amine groups of thiourea– tertiary amine catalysts activate 4-chloroacetoacetate in its enol form and the thiourea moieties activate methyleneindolinones through hydrogen bonding via a transition state (TS) (Scheme 3). Through the dual activation of a thiourea–tertiary amine catalyst, the Michael reaction was realized and generated intermediary Michael adducts A (4a0 and 5a0 ). Different chemoselectivities may be determined by different acidities of the benzylic positions of 4a0 and 5a0 , which led to different reactivities of 4a0 and 5a0 . When the substituent on the nitrogen atom of the oxindole is Boc, the electron withdrawing feature of the group makes the C-3 of the oxindole more acidic and preferable to form enolate ion 4ab in the presence of KHCO3. Enolate ion 4ab was further transformed to spiro-cyclopentanoneoxindole 4a via a-alkylation, while N-methyl protected methyleneindolinone is more preferable to form enolate ion 5ab due to its electron donating feature and gave a 3-substituted oxindole with a tetronic acid motif 5a via O-alkylation. In summary, we have developed a new organocatalyzed enantioselective Michael-alkylation domino reaction of methyleneindolinones with g-halogenated-b-ketoesters. Different main products were obtained by tuning the N-protecting groups on methyleneindolinones. N-Boc protected methyleneindolinones afforded a variety of spiro-cyclopentanoneoxindoles in high yields (up to 96%), good diastereoselectivities (up to 12 : 1 dr) and excellent enantioselectivities (up to 499% ee), while N-alkyl protected ones gave O-alkylated products with tetronic acid scaffolds in excellent enantioselectivities (up to 499% ee). This protocol provides a new method to access spiro-cyclopentanoneoxindoles and 3-substituted oxindoles with tetronic acid motifs. This work was supported by the National Natural Science Foundation of China (No. 21272230) and the Western Light Talent Culture Project.
Notes and references 1 Selected examples: (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) S. S. Girija and Y. D. Zelalem, Chem. Rev., 2012, 112, 6104; (c) R. B. Nicolas, J. B. Joseph and K. F. Annaliese, Org. Biomol. Chem., 2012, 10, 5165; (d) L. Hong and R. Wang, Adv. Synth. Catal., 2013, 355, 1023; (e) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao and L.-Z. Gong, J. Am. Chem. Soc., 2009, 131, 13819; ( f ) Y. Liu, M. Nappi, E. Arceo, S. Vera and P. Melchiorre, J. Am. Chem. Soc., 2011, 133, 15212; (g) Y.-Y. Han, W.-B. Chen, W.-Y. Han, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2012, 14, 490; (h) X.-L. Liu, W.-Y. Han, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2013, 15, 1246; (i) D.-J. Cheng, Y. Ishihara, B. Tan and C. F. Barbas III, ACS Catal., 2014, 4, 743.
Chem. Commun., 2014, 50, 14601--14604 | 14603
View Article Online
Published on 30 September 2014. Downloaded by McGill University on 04/11/2014 17:35:04.
Communication 2 Selected examples: (a) B. M. Trost, N. A. Cramer and S. M. Silverman, J. Am. Chem. Soc., 2007, 129, 12396; (b) X. Li, Y.-M. Li, F. Z. Peng, S.-T. Wu, Z.-Q. Li, Z.-W. Sun, H.-B. Zhang and Z.-H. Shao, Org. Lett., 2011, 13, 6160. 3 Selected example: A. Voituriez, N. Pinto, M. Neel, P. Retailleau and A. Marinetti, Chem. – Eur. J., 2010, 16, 12541. 4 Selected examples: (a) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133, 4672; (b) F. Zhong, X. Han, Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837. 5 Selected examples: (a) B. N. Tan, R. Candeias and C. F. Barbas III, Nat. Chem., 2011, 3, 473; (b) K. Albertshofer, K. E. Anderson and C. F. Barbas III, Org. Lett., 2012, 14, 5968; (c) A. Noole, K. Ilmarinen, ¨rving, M. Lopp and T. Kanger, J. Org. Chem., 2013, 78, 8117. I. Ja 6 Selected example: K. Albertshofer, B. Tan and C. F. Barbas III, Org. Lett., 2012, 14, 1834. 7 Selected examples: (a) Y. M. Li, X. Li, F. Z. Peng, Z. Q. Li, S. T. Wu, Z. W. Sun, H. B. Zhang and Z. H. Shao, Org. Lett., 2011, 13, 6200; (b) B. Zhou, Z. Luo and Y. C. Li, Chem. – Eur. J., 2013, 19, 4428. 8 Selected examples: (a) S. L. Zhang, H. X. Xie, J. Zhu, H. Li, X. S. Zhang, J. Li and W. Wang, Nat. Commun., 2011, 2, 211; (b) W. Sun, G. Zhu, C. Wu, L. Hong and R. Wang, Chem. – Eur. J., 2012, 18, 6737; (c) K. Jiang, B. Tiwari and Y. R. Chi, Org. Lett., 2012, 14, 2382. 9 Selected examples: (a) J. Peng, X. Huang, L. Jiang, H. L. Cui and Y. C. Chen, Org. Lett., 2011, 13, 4584; (b) W. Sun, G. Zhu, L. Hong and R. Wang, Chem. – Eur. J., 2012, 18, 13959.
14604 | Chem. Commun., 2014, 50, 14601--14604
ChemComm 10 (a) L. L. Wang, L. Peng, J. F. Bai, Q. C. Huang, X. Y. Xu and L. X. Wang, Chem. Commun., 2010, 46, 8064; (b) L. L. Wang, L. Peng, J. F. Bai, L. N. Jia, X. Y. Luo, Q. C. Huang, X. Y. Xu and L. X. Wang, Chem. Commun., 2011, 47, 5593; (c) L. L. Wang, J. F. Bai, L. Peng, L. W. Qi, L. N. Jia, Y. L. Guo, X. Y. Luo, X. Y. Xu and L. X. Wang, Chem. Commun., 2012, 48, 5175; (d) Q. L. Wang, L. Peng, F. Y. Wang, M. L. Zhang, L. N. Jia, F. Tian, X. Y. Xu and L. X. Wang, Chem. Commun., 2013, 49, 9422. 11 Selected examples: (a) M. Marigo, S. Bertelsen, A. Landa and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 5475; (b) R. Rios, J. Vesely, ´n, I. Ibrahem, G. L. Zhao and A. Co ´rdova, Tetrahedron Lett., H. Sunde 2007, 48, 5835; (c) N. H. Luo, X. Sun, Y. Y. Yan, S. Z. Nie and M. Yan, Tetrahedron: Asymmetry, 2011, 22, 1536; (d) X. W. Dou, X. Y. Han and Y. X. Lu, Chem. – Eur. J., 2012, 18, 85; (e) Y. Y. Yan, R. J. Lu, J. J. Wang, Y. N. Xuan and M. Yan, Tetrahedron, 2012, 68, 6123; ( f ) H. M. Ma, L. L. Yang, Y. Ni, J. Zhang, C. X. Li, G. W. Zheng, H. Y. Yang and J. H. Xu, Adv. Synth. Catal., 2012, 354, 1765. 12 Selected examples: (a) Y. L. Li, H. Chen, C. L. Shi, D. Q. Shi and S. J. Ji, J. Comb. Chem., 2010, 12, 231; (b) M. Dabiri, Z. N. Tisseh, M. Bahramnejad and A. Bazgir, Ultrason. Sonochem., 2011, 18, 1153; (c) M. Vilches-Herrera, A. Spannenberg, P. Langer and V. O. Iaroshenko, Tetrahedron, 2013, 69, 5955; (d) Q. Wu, H. Feng, D. D. Guo, M. S. Yi, X. H. Wang, B. Jiang and S. J. Tu, J. Heterocycl. Chem., 2013, 50, 599. 13 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672; (b) T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2006, 128, 9413.
This journal is © The Royal Society of Chemistry 2014
