Mg(ClO₄)₂-promoted [4 + 3] cycloaddition of oxindole derivatives with conjugated dienes: concise synthesis of spirocycloheptane oxindole derivatives

Abstract

We herein reported a novel Mg(ClO₄)₂-promoted intermolecular [4 + 3] cycloaddition reaction of oxindole derivatives and cyclopentadiene. This new strategy provides a convenient approach to the concise synthesis of a series of spirocycloheptane oxindole derivatives, with moderate to good yields and high diastereoselectivities.

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The spirooxindole skeletons have drawn tremendous attention among synthetic and medicinal chemists during the past few years due to their functional diversity and their significance in organic synthesis as crucial intermediates.¹ Among them, the spirocycloheptane oxindole frameworks represent ubiquitous structural motifs in a broad range of alkaloids and bioactive compounds (Fig. 1). Most of these alkaloids have been found to exhibit remarkable biological and pharmacological activities. For example, the gelsemine, which was first isolated from Carolina jasmine (Gelsemium sempervirens)² in 1876,³ have recently been found to exhibit potent and specific antinociception in chronic pain by acting at the three spinal glycine receptors.⁴ In this context, the development of flexible synthetic methods for the synthesis of spirocycloheptane oxindole skeletons would thus be beneficial for the synthesis of those bioactive alkaloids.⁵ Although the chemistry of spirooxindole has been studied quite extensively, the investigations are mostly focused on the construction of spirocyclopentane⁶ or spirocyclohexane oxindole⁷ moieties. To date, there has been limited work on the direct construction of spirocycloheptane oxindole frameworks from oxindole derivatives.^8,9

Fig. 1 Structures of natural products possessing the spirocycloheptane oxindole skeleton.

The [4 + 3]-cycloaddition between allylic cations and conjugated dienes has been proved to be a powerful method for the direct synthesis of seven-membered rings.^10–13 The acid-catalysed [4 + 3] cycloaddition reactions of furfurylalcohols and 1,3-diene were first reported by Pattenden in 2009 to construct the 5,5,7-tricyclic skeletons.^13f The substituted furfuryl alcohols could undergo acid-catalysed hydrolysis transformations, and accompanied by displacement of the hydroxyl group, then leading to the furanoxonium ion intermediates, which could react with 1,3-diene via a [4 + 3] cycloaddition.^10e Our group have recently disclosed the intermolecular [4 + 3] cycloaddition of heterocyclic compounds (such as benzofuran, benzothiophene and indole)^14b,c with conjugated dienes to construct various 6,5,7-polycyclic skeletons and their application in the total synthesis of liphagal and frondosin B.^14a In continuation of our previous work, we envisaged that a [4 + 3] cycloaddition reaction between oxindole derived allylic cations and conjugated dienes would result in the straightforward formation of spirocycloheptane oxindoles. Herein, we report a highly diastereoselective [4 + 3] cycloaddition route to the synthesis of spirocycloheptane oxindoles (Scheme 1).

Scheme 1 [4 + 3] cycloaddition reactions of heterocyclic compounds with conjugated dienes.

We initiated our studies using oxindole derivative 3a¹⁵ as dienophiles and cyclopentadiene 4 as conjugated dienes to explore the cycloaddition conditions. Compounds 3a could be readily prepared from N-substituted isatins and 2-methyl furan (for details see ESI†). Selected representative screening results for this model reaction are presented in Table 1. Initially, a variety of frequently used Brønsted acids as well as Lewis acids were examined for the cycloaddition reaction at room temperature in DCM. However, Brønsted acids and most of Lewis acids resulted in no reaction at all (for details see ESI†). Lewis acids such as SnCl₄ and ZnCl₂ could promote the reaction, but resulted in low yields, probably due to the polymerization of dienes or decomposition of the starting materials in these conditions (Table 1, entries 4 and 5). Finally, Mg(ClO₄)₂ was proved to be the optimum Lewis acid. Upon treatment with 1.5 equiv. of anhydrous Mg(ClO₄)₂ in DCM at ambient temperature, 3a underwent cycloaddition with 4 to afford the spirooxindole 5a in 58% yield within 2 h (Table 1, entry 7). Further optimization of the reaction conditions by changing the temperature and solvents did not improve the yields (Table 1, entries 6–10).

Table 1 Optimization of the reaction condition^a

Entry	Conditions	Solvent	T (°C)	Yield^b (%)
a Unless otherwise noted, all reaction was performed with 3 (0.1 mmol, 1.0 eq.), 4 (1.0 mmol, 10.0 eq.) and Lewis acids or Brønsted acids (0.15 mmol, 1.5 eq.) in solvent (15 mL).b Yield of isolated product.c Determined by ^1H NMR (400 MHz) analysis (starting material was decomposed).d NR = no reaction (starting material was recovered); ND = not determined (starting material was decomposed).
1	TFA	DCM	−78 to 0	Trace^c
2	CSA	DCM	−78 to rt	NR^d
3	HClO4	DCM	−78	ND^d
4	SnCl4	DCM	−78 to rt	18
5	ZnCl2	DCM	rt	30
6	Mg(ClO4)2	DCM	0	<5
7	Mg(ClO4)2	DCM	rt	58
8	Mg(ClO4)2	DCM	Reflux	ND^d
9	Mg(ClO4)2	THF	rt	20
10	Mg(ClO4)2	Et2O	rt	25

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Having established the optimal reaction conditions, we then investigated the reactivity of a series of oxindole compounds 3a–l towards cyclopentadiene 4 (Fig. 2). As is shown in Fig. 2, this novel [4 + 3] cycloaddition reaction was found to be applicable for a series of oxindole substrates, and a number of spirocycloheptane oxindole derivatives were afforded in moderate to good yields. The electronic properties of R₁ group on the N-atom of oxindole derivatives clearly influenced the reactivity of substrates. The substrates with electron-donating groups (R₁ = Me/Bn) afforded products 5 in good yields (Fig. 2, 5a–5b), whereas those with electron-withdrawing groups (R₁ = Ac) could not afford the desired products. Similarly, electronic effects of R₂ also substantially affected the yields. In general, the presence of halogen atoms on the phenyl ring obviously reduced the reactivity of substrates (Fig. 2, 5d–5j), therefore the higher temperatures were needed for these reactions. While the electron-donating substituents had positive effects (Fig. 2, 5c and 5k). However, the reaction could not proceed when the substituents on the phenyl ring were two fluorine atoms (Fig. 2, 5l). Notably, this [4 + 3] cycloaddition reaction showed excellent diastereoselectivities for all substrates, and the relative configuration could be determined by the single X-ray crystallographic analysis data of 5a (Fig. 2).

Fig. 2 Scope of the [4 + 3] cycloaddition reaction. ^a Unless otherwise noted, the reaction was performed with 3 (0.1 mmol, 1.0 eq.), 4 (1.0 mmol, 10.0 eq.), and Mg(ClO₄)₂ (0.15 mmol, 1.5 eq.) in DCM (15 mL) at rt. ^b The reaction was performed at refluxing temperature. ^c Diastereomeric ratios were determined by ¹H NMR (400 MHz) analysis. In the experimental results, the diastereoisomer could not be detected in ¹H NMR spectra, therefore we identified the dr as >20 : 1.

The details of the [4 + 3] cycloaddition mechanism have not yet been fully understood. The theoretical results proposed by Winne et al. pointed to a two-step cationic cyclization process,^16a and this can also be supported by Wu's report via the DFT calculations.^16b On the basis of our previous research^14,16e and literature reports,^16a–d a possible mechanism was proposed, as is shown in Scheme 2. Firstly, an allylic cation intermediate 6a could be achieved from the oxindole compounds under Lewis acid conditions. Then, an intermolecular [4 + 3] cycloaddition between 6a and dienes 4 via endo-cycloaddition transition state 8a resulted in the spirocycloheptane oxindole skeleton 5a. Most intermolecular oxyallyl cation-type reactions usually prefer an exo- (or extended) addition mode; while in our experiment, we proposed the transformation was taking place under kinetic control (performed at room temperature or ca. 40 °C), which probably prefer the endo-transition state for maximizing the π–π stacking interaction between the oxindole cation and conjugated cyclopentadiene.¹⁷

Scheme 2 A plausible mechanism for the [4 + 3] cycloaddition reaction.

Conclusions

In summary, we have developed a novel and convenient approach for the construction of spirocycloheptane oxindole skeletons through a Mg(ClO₄)₂-promoted [4 + 3] cycloaddition of oxindole derivatives with conjugated dienes. This method could achieve the concise synthesis of a series of spirocycloheptane oxindoles in moderate yields with high diastereoselectivities. We believe that the strategy demonstrated here may be utilized in the further synthesis of natural products and potential bioactive compounds containing spirocycloheptane oxindole skeletons. Further investigations towards the refinement of the reaction mechanism, as well as applications in total synthesis, are now under way in our lab and will be reported in due course.

Acknowledgements

The authors acknowledge the financial support provided by the National Natural Science Foundation of China (No. 21472078, 21272099, and 21572092). We thank professor Zhi-Xiang Xie (Lanzhou University) for helpful discussion.

Notes and references

1. For reviews of spirooxindole skeletons, see: (a) D.-J. Cheng, Y. Ishihara, B. Tan and C. F. Barbas III, ACS Catal., 2014, 4, 743; (b) A. K. Franz, N. V. Hanhan and N. R. Ball-Jones, ACS Catal., 2013, 3, 540; (c) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748.
2. For reviews of Gelsemium alkaloid, see: (a) B.-F. Zhang, G.-X. Chou and Z.-T. Wang, Helv. Chim. Acta, 2009, 92, 1889; (b) J.-M. Yu, T. Wang, X.-X. Liu, J. Deschamps, J. Flippen-Anderson, X.-B. Liao and J. M. Cook, J. Org. Chem., 2003, 68, 7565; (c) H. Takayama and S. Sakai, J. Synth. Org. Chem., Jpn., 1990, 48, 876.
3. F. L. Sonnenschein, Ber. Dtsch. Chem. Ges., 1876, 9, 1182.
4. J.-Y. Zhang, N. Gong, J.-L. Huang, L.-C. Guo and Y.-X. Wang, Pain, 2013, 154, 2452.
5. For recent selected examples of synthesis of Gelsemine alkaloids: (a) H. Lin and S. J. Danishefsky, Angew. Chem., Int. Ed., 2003, 42, 36; (b) A. Madin, C. J. O'Donnell, T. B. Oh, D. W. Old, L. E. Overman and M. J. Sharp, Angew. Chem., Int. Ed., 1999, 38, 2934; (c) S. Yokoshima, H. Tokuyama and T. Fukuyama, Angew. Chem., Int. Ed., 2000, 39, 4073; (d) X. Zhou, T. Xiao, Y. Iwama and Y. Qin, Angew. Chem., Int. Ed., 2012, 51, 4909; (e) S. Atarashi, J. K. Choi, D. C. Ha, D. J. Hart, D. Kuzmich, C. S. Lee, S. Ramesh and S. C. Wu, J. Am. Chem. Soc., 1997, 119, 6226; (f) W. G. Earley, J. E. Jacobsen, A. Madin, G. P. Meier, C. J. O'Donnell, T. Oh, D. W. Old, L. E. Overman and M. J. Sharp, J. Am. Chem. Soc., 2005, 127, 18046; (g) T. Fukuyama and G. Liu, J. Am. Chem. Soc., 1996, 118, 7426; (h) A. Madin, C. J. O'Donnell, T. Oh, D. W. Old, L. E. Overman and M. J. Sharp, J. Am. Chem. Soc., 2005, 127, 18054; (i) F. W. Ng, H. Lin and S. J. Danishefsky, J. Am. Chem. Soc., 2002, 124, 9812; (j) A. J. Pearson and X.-L. Wang, J. Am. Chem. Soc., 2003, 125, 13326; (k) X. Chen, S. Duan, C. Tao, H. Zhai and F.-G. Qiu, Nat. Commun., 2015, 6, 7204.
6. For recent selected examples of spirocyclopentane oxindole skeletons, see: (a) J. Dugal-Tessier, E. A. O'Bryan, T. B. H. Schroeder, D. T. Cohen and K. A. Scheidt, Angew. Chem., Int. Ed., 2012, 51, 4963; (b) X. Zhao, X. Liu, Q. Xiong, H. Mei, B. Ma, L. Lin and X. Feng, Chem. Commun., 2015, 51, 16076; (c) R. Zhou, K. Zhang, Y. Chen, Q. Meng, Y. Liu, R. Li and Z. He, Chem. Commun., 2015, 51, 14663; (d) Y.-M. Cao, F.-F. Shen, F.-T. Zhang and R. Wang, Chem.–Eur. J., 2013, 19, 1184; (e) W. Guo, X. Wang, B. Zhang, S. Shen, X. Zhou, P. Wang, Y. Liu and C. Li, Chem.–Eur. J., 2014, 20, 8545; (f) J. Xu, L.-D. Shao, D. Li, X. Deng, Y.-C. Liu, Q.-S. Zhao and C. Xia, J. Am. Chem. Soc., 2014, 136, 17962; (g) Y. Tian, L. Tian, X. He, C. Li, X. Jia and J. Li, Org. Lett., 2015, 17, 4874; (h) C. Zheng, W. Yao, Y. Zhang and C. Ma, Org. Lett., 2014, 16, 5028.
7. For recent selected examples of spirocyclohexane oxindole skeletons, see: (a) T.-P. Gao, J.-B. Lin, X.-Q. Hu and P.-F. Xu, Chem. Commun., 2014, 50, 8934; (b) W. Yang and D.-M. Du, Chem. Commun., 2013, 49, 8842; (c) W. Cao, X. Liu, J. Guo, L. Lin and X. Feng, Chem.–Eur. J., 2015, 21, 1632; (d) H.-L. Cui and F. Tanaka, Chem.–Eur. J., 2013, 19, 6213; (e) Y. Shi, A. Lin, H. Mao, Z. Mao, W. Li, H. Hu, C. Zhu and Y. Cheng, Chem.–Eur. J., 2013, 19, 1914; (f) Y.-Y. Han, W.-Y. Han, X. Hou, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2012, 14, 4054; (g) S. Zhao, J.-B. Lin, Y.-Y. Zhao, Y.-M. Liang and P.-F. Xu, Org. Lett., 2014, 16, 1802.
8. (a) P. Drouhin, T. E. Hurst, A. C. Whitwood and R. J. Taylor, Org. Lett., 2014, 16, 4900; (b) L. Wang, Y. Su, X. Xu and W. Zhang, Eur. J. Org. Chem., 2012, 33, 6606; (c) L. Gorokhovik, Neuville and J.-P. Zhu, Org. Lett., 2011, 13, 5536; (d) J. R. Fuchs and R. L. Funk, Org. Lett., 2005, 7, 677; (e) A. C. Peterson and J. M. Cook, Tetrahedron Lett., 1994, 35, 2651; (f) V. Nair, P. M. Treesa, N. P. Rath, A. C. Kunwar, K. S. KiranKumar, A. RaviSankar, M. Vairamani and S. Prabhakar, Tetrahedron, 2002, 58, 7221.
9. G. Zhan, M. L. Shi, Q. He, W. Du and Y. C. Chen, Org. Lett., 2015, 17, 4750.
10. For reviews of [4 + 3] cycloaddition reactions, see: (a) M. Harmata, Acc. Chem. Res., 2001, 34, 595; (b) J. K. Cha and J. Oh, Curr. Org. Chem., 1998, 2, 217; (c) M. Harmata, Chem. Commun., 2010, 46, 8886; (d) M. Harmata, Chem. Commun., 2010, 46, 8904; (e) M. J. Palframan and G. Pattenden, Chem. Commun., 2014, 50, 7223.
11. For recent selected examples of [4 + 3] cycloaddition reactions, see: (a) L. Chen, G.-M. Yang, J. Wang, Q.-F. Jia, J. Wei and Z.-Y. Du, RSC. Adv., 2015, 5, 76696; (b) C. S. Jeffrey, D. Anumandla and C. R. Carson, Org. Lett., 2012, 14, 5764; (c) C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff and C. R. Carson, J. Am. Chem. Soc., 2011, 133, 7688; (d) E. H. Krenske, K. N. Houk and M. Harmata, J. Org. Chem., 2015, 80, 744; (e) B. Lo and P. Chiu, Org. Lett., 2011, 13, 864; (f) A. G. Lohse and R. P. Hsung, Chem.–Eur. J., 2011, 17, 3812; (g) A. G. Lohse, R. P. Hsung, M. D. Leider and S. K. Ghosh, J. Org. Chem., 2011, 76, 3246; (h) J. M. Winne, S. Catak, M. Waroquier and V. Van Speybroeck, Angew. Chem., Int. Ed., 2011, 50, 11990; (i) O. A. Ivanova, E. M. Budynina, A. O. Chagarovskiy, A. E. Kaplun, I. V. Trushkov and M. Y. Melnikov, Adv. Synth. Catal., 2011, 353, 1125.
12. For recent selected examples of [4 + 3] cycloaddition reactions, see: (a) B. W. Gung, D. T. Craft, L. N. Bailey and K. Kirschbaum, Chem.–Eur. J., 2010, 16, 639; (b) X. Han, H. Li, R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51, 10390; (c) D. Shu, W. Song, X. Li and W. Tang, Angew. Chem., Int. Ed., 2013, 52, 3237; (d) B. Song, L.-H. Li, X.-R. Song, Y.-F. Qiu, M.-J. Zhong, P.-X. Zhou and Y.-M. Liang, Chem.–Eur. J., 2014, 20, 5910.
13. For recent selected examples of [4 + 3] cycloaddition reactions, see: (a) A. H. E. Hassan, J. K. Lee, A. N. Pae, S. J. Min and Y. S. Cho, Org. Lett., 2015, 17, 2672; (b) D. R. Laplace, B. Verbraeken, K. Van Hecke and J. M. Winne, Chem.–Eur. J., 2014, 20, 253; (c) Y. Lian, L. C. Miller, S. Born, R. Sarpong and H. M. L. Davies, J. Am. Chem. Soc., 2010, 132, 12422; (d) J. Wang, S.-G. Chen, B.-F. Sun, G. Q. Lin and Y.-J. Shang, Chem.–Eur. J., 2013, 19, 2539; (e) J. Xu, E. J. E. Caro-Diaz and E. A. Theodorakis, Org. Lett., 2010, 12, 3708; (f) G. Pattenden and J. M. Winne, Tetrahedron Lett., 2009, 50, 7310.
14. (a) J. Zhang, L. Li, Y. Wang, W. Wang, J. Xue and Y. Li, Org. Lett., 2012, 14, 4528; (b) W. Gong, Y. Liu, J. Zhang, Y. Jiao, J. Xue and Y. Li, Chem.–Asian J., 2013, 8, 546; (c) J. Zhang, J. Shao, J. Xue, Y. Wang and Y. Li, RSC Adv., 2014, 4, 63850.
15. We have tried many types of allylic alcohols: such as ethenyl-, alkynyl-, phenyl-, thienyl-, furyl-, benzothiophenyl- group, etc. The unsubstituted furyl-oxindole derivatives could not exist stably for the C2 position of furan is the most reactive site towards electrophiles. And the others could not react with cyclopentadiene under the optimal reaction conditions to achieve the expected spirocycloheptane oxindole skeletons (for details see ESI†).
16. (a) J. M. Winne, S. Catak, M. Waroquier and V. van Speybroeck, Angew. Chem., Int. Ed., 2011, 50, 11990; (b) X. Han, H. Li, R. P. Hughes and J. Wu, Angew. Chem., Int. Ed., 2012, 51, 10390; (c) M. J. Palframan and G. Pattenden, Tetrahedron Lett., 2013, 52, 324; (d) G. Pattenden and M. Palframan, Synlett, 2013, 24, 2720; (e) In the experimental results, when we used thiophenes as dienes, only a Friedel–Crafts intermolecular alkylation reaction occurred, giving an ordinary electrophilic adducts 9a (determined by the single X-ray crystallographic analysis, for details see ESI†). We expected that these results might support for a two-step pathway mechanism of the intermolecular [4 + 3] cycloaddition reactions (for details see ESI†).
17. (a) M. Harmata, S. Elomari and C. L. Barnes, J. Am. Chem. Soc., 1996, 118, 2860; (b) J. I. Garcia, J. A. Mayoral and L. Salvatella, Acc. Chem. Res., 2000, 33, 658.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1434481. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra03259a

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