Allylation and alkylation of oxindoleketimines via imine umpolung strategy

Mei-Hua Shen Chen Li Qing-Song Xu Bin Guo Rui Wang Xiaoqian Liu Hua-Dong Xu Defeng Xu

Citation:  Mei-Hua Shen, Chen Li, Qing-Song Xu, Bin Guo, Rui Wang, Xiaoqian Liu, Hua-Dong Xu, Defeng Xu. Allylation and alkylation of oxindoleketimines via imine umpolung strategy[J]. Chinese Chemical Letters, 2021, 32(7): 2313-2316. doi: 10.1016/j.cclet.2021.02.026 shu

Allylation and alkylation of oxindoleketimines via imine umpolung strategy


  • Occurring widely both in nature products and synthetic agents of biologic significance, the structurally unique 3-substituted 3-amino-2-oxindole moiety is becoming a popular and privileged substructure in medicinal chemistry [1-7], as embodied by Chartellines A–C [8], gastrin receptor antagonist AG-041R [9], anti-bacterial agent spirooxindole 1 [10], anti-cancer agent 2 [11] and HIV protease inhibitor 3 [12] (Fig. 1). In the past 15 years, developing new protocols for the construction of this framework has constituted an active topic among synthetic chemists leading to a plethora of creative methods [1, 2]. Almost all of literature syntheses fall in roughly three strategies (Scheme 1). Firstly, 3-alkyl oxindolate anion 5 reacts with appropriate electrophilic nitrogen sources leading to the formation of tetra-substituted oxindoles 4 (path a) [13]. Alternatively, alkylation of 3-amino oxindolate anion 6 with C-electrophiles can afford 3-amino-2-oxindole as well (path b) [14-32]. The addition of alkyl nucleophiles over the convenient oxindole imines 7 provides the third and probably the most widely adopted tactic (path c) [33-54]. Impressed by the umpolung reaction of imines [55-60], which could construct a C(sp3)-C(sp3) and a C(sp3)-N bond simultaneously on a single carbon through the immediacy of azaallyl anion [61-69], we argued that this chemistry, if effective with oxindole (8) derived ketimine 9, would provide a facile access to 3-alkyl-3-amino-2-oxindole considering the readily available oxindoles (path d). Herein, we would like to disclose our progress along this direction and report on a new preparative protocol for the core substructure under discussion.

    Figure 1

    Figure 1.  Selected 3-alkyl-3-amino oxindoles of biological importance.

    Scheme 1

    Scheme 1.  Conventional and imine umpolung strategies toward 3-alkyl-3-amino oxindole.

    Our studies began with exploring the reaction of N-diphenylmethyl ketimine 9a with cinnamyl bromide 11a (Table 1). Almost no reaction was detected after the introduction of 11a into a premixed solution of 9a with 2 equiv. Cs2CO3 in dichloromethane followed by stirring for 48 h at room temperature (entry 1). Employment of NaOH powder in place of Cs2CO3 resulted in a mixture with gradually deepened red color in 30 min. Upon addition of the allyl bromide, the red color faded away in 2 days and the desired 3-allyl-3-amino oxindole 4a was obtained in a 10% yield after hydrolysis (entry 2). Impressively, an immediate color change to dark red took place with KOH as the base and a remarkable increment in the yield to 52% was observed (entry 3), manifesting the noticeable beneficial effects of the potassium counter ion on the reaction in comparison with its sodium congener. By using t-BuOK instead, instantaneous color change took place resulting in a further yield improvement to 67% (entry 4). Evaluation of several common solvents spanning a range of polarity (PhMe, THF, dioxane, MeCN, DMF) enabled the quick identification of THF as the optimal reaction medium, furnishing a clean reaction with a yield as high as 85% in only 12 h (entries 5–9). Cutting down the quantity of electrophile 11a to 1.2 equiv. led to a slight drop in yield (entry 10). On the other hand, base deduction to 1.2 equiv. caused a drastic yield decline (entry 11), while triple-fold excess of t-BuOK could further promote the yield to 93% (entry 12). The appearance of the characteristic red color proved the formation and persistence of the corresponding 2-azaallyl anion 10a. By now, the proof-of-concept reaction for umpolung alkylation of oxindole ketimine with C-electrophile was realized.

    Table 1

    Table 1.  Proof of concept and condition optimization.a
    DownLoad: CSV

    With optimized conditions in hand for the C3-alkylation of oxindole imine, we proceed to explore the scope of the ketimines (Scheme 2). As expected, 9b with NBn group reacted smoothly to give 4b in a high yield (84%) after column chromatography. The reaction of 9c afforded product 4c in a yield of 73%, and this perceptible yield decrease might attribute to the less stable NPh lactam group. Oxindole imines 9d-f carrying electron releasing substituents MeO, Me and t-Bu at C5 reacted equally well with cinnamyl bromide to give 4d-f in excellent yields (81%–89%). Halogenation at the same position did not exert any adverse effects on this process as evidenced by constantly high conversions of 9g-j to products 4g-j. Gratifyingly, with strong electron withdrawing ester and nitro groups at C5, 4k and 4l were obtained in 83% and 87% yield respectively from corresponding substrates 9k and 9l. These results shown that not only halides but also ester and nitro groups are compatible with the current basic conditions. The high yields of 4m and 4n indicated that substitution at C7 could barely affect the reaction outcomes. 4-Br oxindole derived ketimine 9o achieved 4o in 81% yield as well, in spite of the potential hindrance around the reacting site. These functionalities provide convenient handles for further chemical manipulations of these useful products.

    Scheme 2

    Scheme 2.  The scope of oxindole ketimines. On a 0.25 mmol scale, isolated yields were reported. aHydrolyzed with AcOH in MeOH.

    Next, with 9a as the azaallyl anion precursor, we turned to explore the scope of electrophiles for this coupling process (Scheme 3). ortho-, meta- and para-Brominated cinnamyl bromides 11b-d as well as the para-chloro homologue 11e all reacted equally well as their parent bromide 11a, delivering 4′b-e in high yields (81%–88%). With 4-methoxylated cinmmyl bromide 11f, a similar yield of 4′f was obtained. In the comparison with allyl bromide (11g), allyl iodine (11g') served as a better electrophile in terms of reaction yield (74% vs. 82%). Other aliphatic allyl halides such as (E)-crotyl chloride (11h), prenyl bromide (11i) and methylallyl chloride (11j) are all viable electrophiles affording 3-allyl-3-amino oxindoles 4′h-j without any difficulties. The modest yields observed in these cases might be due to the relatively more labile alkenyl groups in the strong acidic hydrolyzing conditions. 3-Amino-3-propargyl oxindoles 4′k-m were obtained all in good yields under the same conditions by coupling with related propargyl electrophiles 11k-m (66%–77%). Besides halides, sulfonate could also serve as a good leaving group as evidenced by the efficient coupling reaction of 9a with 2-butynyl mesylate (11l, 77% yield). At last, the azaallyl anion mediated nucleophilic C-alkylation of 9a with a series of benzyl halides also proceeded smoothly, giving rise to 4′n-r in high to excellent yields (71%–86%). The hindrance imposed by the o-Cl group in 11p might account for the 10% drop in yield of 4′p when compared with that observed for 4′o.

    Scheme 3

    Scheme 3.  The scope of electrophiles. On a 0.25 mmol scale, isolated yields were reported. a2 h. b6 equiv. of t-BuOK was used.

    In order to figure out the viability of N-unprotected substrates for this protocol, NH free ketimine 9p was submmitted to the standard conditions employing allyl bromide 11g (2 equiv.) as the electrophile. Double allylated product 4p was isolated in a nice yield of 59% (Scheme 4a). To further demonstrate the usefulness of the current reaction in organic synthesis [70, 71], gram-scale reaction was carried out with 9a. Pleasingly, 4′g was smoothly collected in 71% yield (Scheme 4b).

    Scheme 4

    Scheme 4.  Reaction of NH substrate and gram-scale synthesis.

    The presence of the versatile allyl and propargyl groups endues the product with diverse potential transformations (Scheme 5). For example, treatment of 4′i with I2 in the presence of NaHCO3 in MeCN accomplished spirooxindole 12a successfully (Scheme 5a) [72]. By applying Ullman-Ma coupling reaction [73, 74], 4′q was also smoothly converted into benzofused spiroxindole 12b (Scheme 5b). It is worth to note that spirooxindoles make up a significant and highly wanted class of indole derivatives in the medicinal chemistry perspective [75-77]. These showcases underscore the usefulness of current reactions.

    Scheme 5

    Scheme 5.  Examples of application of products in synthesis.

    In summary, a convenient method for the synthesis of important 3-amino-3-allyl/alkyl oxindoles has been developed by using an imine umpolung strategy. N-Diphenylmethyl imino oxindoles can be allylated or alkylated successfully with carbon based electrophiles at the C3 position after treating with an appropriate base. This strategy of construction of oxindole quaternary C3 is realized through the intermediacy of azaallyl anions and provide a complementary access to 3-substituted 3-amino-oxidoles. Moreover, the products are also versatile molecules for further transformations, for example, biological important spirooxindoles can be obtained readily by one-step reactions.

    The authors report no declarations of interest.

    The authors thank the National Natural Science Foundation of China (No. 21672027) for financial support. This work is also supported by High-Level Entrepreneurial Talent Team of Jiangsu Province (No. 2017-37).

    1. [1]

      J. Kaur, B.P. Kaur, S.S. Chimni, Org. Biomol. Chem. 18 (2020) 4692-4708. doi: 10.1039/d0ob00777c

    2. [2]

      J. Kaur, S.S. Chimni, S. Mahajan, et al., RSC Adv. 5 (2015) 52481-52496. doi: 10.1039/C5RA06969F

    3. [3]

      M. Rottmann, C. McNamara, B.K.S. Yeung, et al., Science 329 (2010) 1175-1180. doi: 10.1126/science.1193225

    4. [4]

      S. Crosignani, C. Jorand-Lebrun, P. Page, et al., ACS Med. Chem. Lett. 2 (2011) 644-649. doi: 10.1021/ml2001196

    5. [5]

      S.U. Maheswari, K. Balamurugan, S. Perumal, et al., Bioorg. Med. Chem. Lett. 20 (2010) 7278-7282. doi: 10.1016/j.bmcl.2010.10.080

    6. [6]

      P. Prasanna, K. Balamurugan, S. Perumal, et al., Eur. J. Med. Chem. 45 (2010) 5653-5661. doi: 10.1016/j.ejmech.2010.09.019

    7. [7]

      R.R. Kumar, S. Perumal, P. Senthilkumar, et al., J. Med. Chem. 51 (2008) 5731-5735. doi: 10.1021/jm800545k

    8. [8]

      U. Anthoni, L. Chevolot, C. Larsen, et al., J. Org. Chem. 52 (1987) 4709-4712. doi: 10.1021/jo00230a010

    9. [9]

      M. Ochi, K. Kawasaki, H. Kataoka, et al., Biochem. Biophys. Res. Commun. 283 (2001) 1118-1123. doi: 10.1006/bbrc.2001.4911

    10. [10]

      R.S. Kumar, S.M. Rajesh, S. Perumal, et al., Eur. J. Med. Chem. 45 (2010) 411-422. doi: 10.1016/j.ejmech.2009.09.044

    11. [11]

      L. Chen, J. Zhang, Z. Zhang, et al., WO2008034736A2, 2008.

    12. [12]

      A.K. Ghosh, G. Schiltz, R.S. Perali, et al., Bioorg. Med. Chem. Lett. 16 (2006) 1869-1873. doi: 10.1016/j.bmcl.2006.01.011

    13. [13]

      K. Ohmatsu, Y. Ando, T. Nakashima, et al., Chem 1 (2016) 802-810. doi: 10.1016/j.chempr.2016.10.012

    14. [14]

      J. Chen, B.Q. Huang, Z.Q. Wang, et al., Org. Lett. 21 (2019) 9742-9746. doi: 10.1021/acs.orglett.9b03911

    15. [15]

      S. Chen, G.L. Wang, S. -W. Xu, et al., Org. Biomol. Chem. 17 (2019) 6551-6556. doi: 10.1039/c9ob01203f

    16. [16]

      W.T. Fan, N.K. Li, L. Xu, et al., Org. Lett. 19 (2017) 6626-6629. doi: 10.1021/acs.orglett.7b03341

    17. [17]

      H.Z. Gui, Y. Wei, M. Shi, Org. Biomol. Chem. 16 (2018) 9218-9222. doi: 10.1039/c8ob02748j

    18. [18]

      H.Z. Gui, X.Y. Wu, Y. Wei, et al., Adv. Synth. Catal. 361 (2019) 5466-5471. doi: 10.1002/adsc.201901124

    19. [19]

      K.Q. Hou, F. Zhou, X.P. Chen, et al., J. Org. Chem. 85 (2020) 9661-9671. doi: 10.1021/acs.joc.0c00981

    20. [20]

      C.W. Lei, C.B. Zhang, Z.H. Wang, et al., Org. Chem. Front. 7 (2020) 499-506. doi: 10.1039/c9qo01039d

    21. [21]

      N.K. Li, W.T. Fan, J.Q. Zhang, et al., Chem. Commun. (Camb. ) 54 (2018) 2260-2263. doi: 10.1039/C7CC09489B

    22. [22]

      N. Lin, X.W. Long, Q. Chen, et al., Tetrahedron 74 (2018) 3734-3741. doi: 10.1016/j.tet.2018.05.052

    23. [23]

      Y. Lin, B.L. Zhao, D. -M. Du, J. Org. Chem. 83 (2018) 7741-7750. doi: 10.1021/acs.joc.8b00632

    24. [24]

      X.J. Song, H.X. Ren, M. Xiang, et al., J. Org. Chem. 85 (2020) 9290-9300. doi: 10.1021/acs.joc.9b03337

    25. [25]

      Y.H. Wang, J.S. Tian, P.W. Tan, et al., Angew. Chem. Int. Ed. 59 (2020) 1634-1643. doi: 10.1002/anie.201910864

    26. [26]

      X.C. Yang, M.M. Liu, F. Mathey, et al., J. Org. Chem. 84 (2019) 7762-7775. doi: 10.1021/acs.joc.9b00645

    27. [27]

      Z.H. You, Y.H. Chen, Y. Tang, et al., Org. Lett. 20 (2018) 6682-6686. doi: 10.1021/acs.orglett.8b02731

    28. [28]

      B.L. Zhao, D.M. Du, Adv. Synth. Catal. 361 (2019) 3412-3419. doi: 10.1002/adsc.201900218

    29. [29]

      J.Q. Zhao, X.J. Zhou, Y.Z. Chen, et al., Adv. Synth. Catal. 360 (2018) 2482-2487. doi: 10.1002/adsc.201800266

    30. [30]

      J.Q. Zhao, X.J. Zhou, Y. Zhou, et al., Org. Lett. 20 (2018) 909-912. doi: 10.1021/acs.orglett.7b03667

    31. [31]

      Y. Zhu, J. Guo, S. Jin, et al., Org. Biomol. Chem. 16 (2018) 1751-1759. doi: 10.1039/C8OB00306H

    32. [32]

      X. Zuo, S. Chen, S.W. Xu, et al., Synthesis 51 (2019) 2339-2350. doi: 10.1055/s-0037-1610875

    33. [33]

      T. Arai, K. Araseki, J. Kakino, Org. Lett. 21 (2019) 8572-8576. doi: 10.1021/acs.orglett.9b03148

    34. [34]

      Y. Fan, J. Lu, F. Sha, et al., J. Org. Chem. 84 (2019) 11639-11648. doi: 10.1021/acs.joc.9b01566

    35. [35]

      S. Hajra, S. Laskar, B. Jana, Chem. Eur. J. 25 (2019) 14688-14693. doi: 10.1002/chem.201903512

    36. [36]

      T. Kang, W. Cao, L. Hou, et al., Angew. Chem. Int. Ed. 58 (2019) 2464-2468. doi: 10.1002/anie.201810961

    37. [37]

      J. Wang, Y. Liu, Y. Liu, et al., Tetrahedron 75 (2019) 2883-2892. doi: 10.1016/j.tet.2019.04.015

    38. [38]

      J. Wang, Q. Zhang, B. Zhou, et al., iScience 16 (2019) 511-523. doi: 10.1016/j.isci.2019.06.006

    39. [39]

      G. Wu, H. Xu, Z. Liu, et al., Org. Lett. 21 (2019) 7708-7712. doi: 10.1021/acs.orglett.9b02440

    40. [40]

      Y.N. Yu, W.Y. Qi, C.Y. Wu, et al., Org. Lett. 21 (2019) 7493-7497. doi: 10.1021/acs.orglett.9b02787

    41. [41]

      J. Zhou, G.D. Zhu, L. Wang, et al., Org. Lett. 21 (2019) 8662-8666. doi: 10.1021/acs.orglett.9b03276

    42. [42]

      J. Zhu, S. Fang, S. Jin, et al., Org. Biomol. Chem. 17 (2019) 8745-8748. doi: 10.1039/c9ob01347d

    43. [43]

      L. Cai, X. Liu, J. Wang, et al., Chem. Commun. (Camb. ) 56 (2020) 10361-10364. doi: 10.1039/d0cc04966b

    44. [44]

      V. Filatov, M. Kukushkin, J. Kuznetsova, et al., RSC Adv. 10 (2020) 14122-14133. doi: 10.1039/d0ra02374d

    45. [45]

      Z. Li, J. Peng, C. He, et al., J. Org. Chem. 85 (2020) 3894-3901. doi: 10.1021/acs.joc.9b03000

    46. [46]

      C. Liu, F.X. Tan, J. Zhou, et al., Org. Lett. 22 (2020) 2173-2177. doi: 10.1021/acs.orglett.0c00262

    47. [47]

      S. Nakamura, K. Matsuzaka, T. Hatanaka, et al., Org. Lett. 22 (2020) 2868-2872. doi: 10.1021/acs.orglett.0c00289

    48. [48]

      G.Y. Ran, C. Chen, X.X. Yang, et al., Org. Lett. 22 (2020) 4732-4736. doi: 10.1021/acs.orglett.0c01534

    49. [49]

      V.U.B. Rao, S. Singh, K.N. Tripathi, et al., Synthesis 52 (2020) 2551-2562. doi: 10.1055/s-0040-1707907

    50. [50]

      M. Rodriguez-Rodriguez, A. Maestro, J.M. Andres, et al., Adv. Synth. Catal. 362 (2020) 2744-2754. doi: 10.1002/adsc.202000238

    51. [51]

      R. Yonesaki, I. Kusagawa, H. Morimoto, et al., Chem. Asian J. 15 (2020) 499-502. doi: 10.1002/asia.201901745

    52. [52]

      H. Zhang, Y. Luo, C. Zhu, et al., Org. Lett. 22 (2020) 5217-5222. doi: 10.1021/acs.orglett.0c01857

    53. [53]

      Y. Zhao, L. Cai, T. Huang, et al., Adv. Synth. Catal. 362 (2020) 1309-1316. doi: 10.1002/adsc.201901380

    54. [54]

      W.R. Zhu, K. Liu, J. Weng, et al., Org. Lett. 22 (2020) 5014-5019. doi: 10.1021/acs.orglett.0c01578

    55. [55]

      Y. Wu, L. Hu, Z. Li, et al., Nature 523 (2015) 445-450. doi: 10.1038/nature14617

    56. [56]

      Y. Wang, L.F. Deng, X. Zhang, et al., Org. Lett. 21 (2019) 6951-6956. doi: 10.1021/acs.orglett.9b02550

    57. [57]

      L.M. Shi, X.S. Sun, C. Shen, et al., Org. Lett. 21 (2019) 4842-4848. doi: 10.1021/acs.orglett.9b01738

    58. [58]

      J. Liu, C.G. Cao, H.B. Sun, et al., J. Am. Chem. Soc. 138 (2016) 13103-13106. doi: 10.1021/jacs.6b05288

    59. [59]

      C.X. Zhuo, A. Fürstner, J. Am. Chem. Soc. 140 (2018) 10514-10523. doi: 10.1021/jacs.8b05094

    60. [60]

      X. Li, J. Su, Z. Liu, et al., Org. Lett. 18 (2016) 956-959. doi: 10.1021/acs.orglett.5b03566

    61. [61]

      W.W. Chen, B. Zhao, Synlett 31 (2020) 1543-1550. doi: 10.1055/s-0040-1707157

    62. [62]

      S. Tang, X. Zhang, J. Sun, et al., Chem. Rev. 118 (2018) 10393-10457. doi: 10.1021/acs.chemrev.8b00349

    63. [63]

      X.S. Sun, X.H. Wang, H.Y. Tao, et al., Chem. Sci. 11 (2020) 10984-10990. doi: 10.1039/d0sc04685j

    64. [64]

      K. Li, A.E. Weber, L. Tseng, et al., Org. Lett. 19 (2017) 4239-4242. doi: 10.1021/acs.orglett.7b01886

    65. [65]

      L.R. Reddy, S. Kotturi, R. Shenoy, et al., Org. Lett. 20 (2018) 5423-5426. doi: 10.1021/acs.orglett.8b02331

    66. [66]

      S. Wang, X. Qian, Y. Chang, et al., J. Org. Chem. 83 (2018) 4054-4069. doi: 10.1021/acs.joc.8b00491

    67. [67]

      M. Zhan, X. Pu, B. He, et al., Org. Lett. 20 (2018) 5857-5860. doi: 10.1021/acs.orglett.8b02536

    68. [68]

      P.E. Daniel, A.E. Weber, S.J. Malcolmson, Org. Lett. 19 (2017) 3490-3493. doi: 10.1021/acs.orglett.7b01471

    69. [69]

      P. Chen, Z. Yue, J. Zhang, et al., Angew. Chem. Int. Ed. 55 (2016) 13316-13320. doi: 10.1002/anie.201607918

    70. [70]

      S. Peng, Y.X. Song, J.Y. He, et al., Chin. Chem. Lett. 30 (2019) 2287-2290.

    71. [71]

      Z. Cao, Q. Zhu, Y.W. Lin, et al., Chin. Chem. Lett. 30 (2019) 2132-2138.

    72. [72]

      D.F. Li, H.S. Jin, J.R. Zhang, et al., Eur. J. Org. Chem. 2018 (2018) 4787-4794. doi: 10.1002/ejoc.201800881

    73. [73]

      D. Ma, Q. Cai, Org. Lett. 5 (2003) 3799-3802.

    74. [74]

      D. Ma, Y. Zhang, J. Yao, et al., J. Am. Chem. Soc. 120 (1998) 12459-12467.

    75. [75]

      S.S. Panda, R.A. Jones, P. Bachawala, et al., Mini-Rev. Med. Chem. 17 (2017) 1515-1536.

    76. [76]

      Y.T. Yang, J.F. Zhu, G. Liao, et al., Curr. Med. Chem. 25 (2018) 2233-2244. doi: 10.2174/0929867325666171129131311

    77. [77]

      L.M. Zhou, R.Y. Qu, G.F. Yang, Expert Opin. Drug Discovery 15 (2020) 603-625. doi: 10.1080/17460441.2020.1733526

  • Figure 1  Selected 3-alkyl-3-amino oxindoles of biological importance.

    Scheme 1  Conventional and imine umpolung strategies toward 3-alkyl-3-amino oxindole.

    Scheme 2  The scope of oxindole ketimines. On a 0.25 mmol scale, isolated yields were reported. aHydrolyzed with AcOH in MeOH.

    Scheme 3  The scope of electrophiles. On a 0.25 mmol scale, isolated yields were reported. a2 h. b6 equiv. of t-BuOK was used.

    Scheme 4  Reaction of NH substrate and gram-scale synthesis.

    Scheme 5  Examples of application of products in synthesis.

    Table 1.  Proof of concept and condition optimization.a

    下载: 导出CSV
  • 加载中
  • PDF下载量:  5
  • 文章访问数:  589
  • HTML全文浏览量:  142
  • 发布日期:  2021-07-15
  • 收稿日期:  2020-12-01
  • 接受日期:  2021-02-10
  • 修回日期:  2021-02-03
  • 网络出版日期:  2021-02-16
通讯作者: 陈斌,
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索