Visible-light photoredox catalyzed synthesis of pyrroloisoquinolines via organocatalytic oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade with Rose Bengal

  1. Carlos Vila,
  2. Jonathan Lau and
  3. Magnus Rueping

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany

  1. Corresponding author email

This article is part of the Thematic Series "Organic synthesis using photoredox catalysis".

Guest Editor: A. G. Griesbeck
Beilstein J. Org. Chem. 2014, 10, 1233–1238. https://doi.org/10.3762/bjoc.10.122
Received 20 Feb 2014, Accepted 30 Apr 2014, Published 27 May 2014

Abstract

Pyrrolo[2,1-a]isoquinoline alkaloids have been prepared via a visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative aromatization cascade using Rose Bengal as an organo-photocatalyst. A variety of pyrroloisoquinolines have been obtained in good yields under mild and metal-free reaction conditions.

Keywords: alkaloids; [3 + 2] cycloaddition; organocatalysis; oxidation; photochemistry; photoredox catalysis; Rose Bengal; visible-light

Introduction

Pyrrolo[2,1-a]isoquinolines constitute the core structure of the natural products family lamellarin alkaloids (Figure 1) [1-4]. These alkaloids display numerous biological activities such as inhibitor of human topoisomerase I by lamellarin D [5] or inhibition of HIV integrase by lamellarin α-20-sulfate [6,7]. Moreover lamellarin I and lamellarin K also showed potential antitumor activities [8,9]. Due to their potential biological activities, the synthesis of pyrrolo[2,1-a]isoquinolines has become a very interesting, important and attractive goal in organic synthesis [10-20]. For example, dipolar [3 + 2] cycloaddition using azomethine ylides [21] is a powerful class of reactions that permits the synthesis of structural complex molecules in a straightforward way and has been used for the efficient synthesis of this type of compounds [22-26]. Recently, several metal mediated syntheses using a [3 + 2] cycloaddition reaction have been described in the literature. Porco Jr. et al. [27] described a silver-catalyzed cycloisomerization/dipolar cycloaddition for the synthesis of the pyrrolo[2,1-a]isoquinolines. Wang and co-workers described a copper catalyzed oxidation/[3 + 2] cycloaddition/aromatization cascade [28]. Also, Xiao disclosed a very elegant oxidation/[3 + 2] cycloaddition/aromatization cascade catalyzed by [Ru(bpy)3]3+ under irradiation with visible light [29]. In this context, very recently Zhao reported the same reaction using C60-Bodipy hybrids [30] and porous material immobilized iodo-Bodipy [31] as photocatalysts, obtaining in both cases good yields for different pyrrolo[2,1-a]isoquinolines. Finally, Lu presented in 2013 a dirhodium complex for the synthesis of these compounds [32]. Despite these elegant and important syntheses of pyrrolo[2,1-a]isoquinolines through dipolar [3 + 2] cycloaddition, the development of metal-free syntheses using visible light photoredox catalysis with simple organic dyes remained unexplored. Visible-light photoredox catalysis has emerged as an important field and has attracted increasing attention in recent years [33-42]. Thus, in the last years spectacular advances in visible-light photoredox catalysis have been made and this kind of catalysis has become a powerful tool in organic synthesis. In this context, the use of organic dyes as photoredox catalysts [40-42] has been demonstrated by several groups [43-61] and became a useful alternative to the inorganic photoredox catalysts that are expensive and sometimes toxic. The organic dyes have very important qualities such as being inexpensive, environmentally friendly and easy to handle. As a part of our ongoing research on photoredox catalysis [62-72], we herein present a synthesis of pyrrolo[2,1-a]isoquinolines through an oxidation/[3+2] cycloaddition/aromatization cascade catalyzed by Rose Bengal under irradiation with green LEDs.

[1860-5397-10-122-1]

Figure 1: Representative examples of lamellarin alkaloids.

Results and Discussion

Initially, we focused on the reaction between methyl dihydroisoquinoline ester 1a and N-methylmaleimide (2a) catalyzed by Rose Bengal. Although the [3 + 2] cycloaddition occurs smoothly in the presence of Rose Bengal (5 mol %) in acetonitrile under irradiation with visible light, the reaction was not selective affording the dihydropyrrolo[2,1-a]isoquinoline 3aa in 35% yield and the hexahydropyrrolo[2,1-a]isoquinoline 4aa in 26% yield, after column chromatography (Scheme 1).

[1860-5397-10-122-i1]

Scheme 1: Photocatalytic metal free construction of pyrrolo[2,1-a]isoquinolines.

In order to improve the selectivity of the reaction to the aromatized product 3aa, N-bromosuccinimide was added to the reaction mixture when the starting materials were completely consumed [29-31,73]. In this case the desired product 3aa was obtained in 72% yield (Table 1, entry 1). Other organic dyes such as Rhodamine B or Eosin Y were less efficient compared to Rose Bengal (Table 1, entries 2 and 3, respectively). Several solvents were tested without an improvement in the yield of the product (Table 1, entries 4–9). Finally, after tuning the relative amounts of the reagents, the product 3aa was isolated in 76% yield (Table 1, entry 12).

Table 1: Optimization of the reaction conditions.a

[Graphic 1]
Entry Catalyst Solvent Yield (%)b
1 Rose Bengal CH3CN 72
2 Rhodamine B CH3CN 11
3 Eosin Y CH3CN 40
4 Rose Bengal THF 29
5 Rose Bengal CH2Cl2 26
6 Rose Bengal toluene 14
7 Rose Bengal DMF 65
8 Rose Bengal MeOH 52
9 Rose Bengal EtOAc 16
10c Rose Bengal CH3CN 64
11d Rose Bengal CH3CN 60
12e Rose Bengal CH3CN 76

aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), organic dye (5 mol %), solvent (1 mL), green LEDs irradiation for 24 hours. NBS (1.1 equiv) was added to the reaction mixture and stirring was continued for 1 hour. bYields of the isolated products after column chromatography. c1.25 equiv of 1a was used. d1.25 equiv of 2a was used. e1.1 equiv of 1a was used.

With the optimal conditions in hand, we examined the substrate scope for the photoreaction catalyzed by Rose Bengal (Scheme 2). Various tetrahydroisoquinolines with different electron-withdrawing groups (R2) such as methyl ester (1a), ethyl ester (1b), tert-butyl ester (1c), cyano (1d) or aromatic ketone (1e) were reacted with N-methylmaleimide (2a) and gave the corresponding products 3 in moderate to good yields. In addition, different N-substituted maleimides were tested under the optimized reaction conditions to give the corresponding products with good yields. Incorporation of methoxy groups at C-6 and C-7 in the dihydroisoquinoline core was well tolerated, affording the corresponding product 3fa in 68% yield.

[1860-5397-10-122-i2]

Scheme 2: Evaluation of the substrate scope.

To demonstrate the synthetic utility of the oxidation/[3 + 2] cycloaddition/aromatization cascade we examined other dipolarophiles such as activated alkynes 5. In this case, the addition of NBS was not necessary, and the corresponding products 6 were isolated in moderate yields (Scheme 3).

[1860-5397-10-122-i3]

Scheme 3: Evaluation of the substrate scope with activated alkynes.

Conclusion

In conclusion, we have developed a metal-free photoredox oxidation/[3 + 2] dipolar cycloaddition/oxidative aromatization cascade catalyzed by Rose Bengal using visible-light. This protocol offers a “green” and straightforward synthesis of pyrrolo[2,1-a]isoquinolines starting from readily available maleimides and tetrahydroisoquinolines. Further investigations to expand the scope and potential of this methodology are underway in our laboratory.

Supporting Information

Supporting Information File 1: Experimental details and characterization of the synthesized compounds.
Format: PDF Size: 665.1 KB Download

References

  1. Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363–378. doi:10.2174/1568011043352939
    Return to citation in text: [1]
  2. Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005, 37, 411–445. doi:10.1080/00304940509354977
    Return to citation in text: [1]
  3. Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264–287. doi:10.1021/cr078199m
    Return to citation in text: [1]
  4. Pla, D.; Albericio, F.; Alvarez, M. Anti-Cancer Agents Med. Chem. 2008, 8, 746–760. doi:10.2174/187152008785914789
    Return to citation in text: [1]
  5. Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796–3807. doi:10.1021/jm049060w
    Return to citation in text: [1]
  6. Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bushman, F. D.; Venkateswarlu, Y.; Faulkner, D. J. Med. Chem. 1999, 42, 1901–1907. doi:10.1021/jm9806650
    Return to citation in text: [1]
  7. Aubry, A.; Pan, X.-S.; Fisher, L. M.; Jarlier, V.; Cambau, E. Antimicrob. Agents Chemother. 2004, 48, 1281–1288. doi:10.1128/AAC.48.4.1281-1288.2004
    Return to citation in text: [1]
  8. Reddy, S. M.; Srinivasulu, M.; Satanarayana, N.; Kondapi, A. K.; Venkateswarlu, Y. Tetrahedron 2005, 61, 9242–9247. doi:10.1016/j.tet.2005.07.067
    Return to citation in text: [1]
  9. Quesada, A. R.; Garcia Grávalos, M. D.; Fernández Puentes, J. L. Br. J. Cancer 1996, 74, 677–682. doi:10.1038/bjc.1996.421
    Return to citation in text: [1]
  10. Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1997, 36, 155–156. doi:10.1002/anie.199701551
    Return to citation in text: [1]
  11. Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S. Angew. Chem., Int. Ed. 2004, 43, 866–868. doi:10.1002/anie.200352043
    Return to citation in text: [1]
  12. Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54–62. doi:10.1021/ja982078+
    Return to citation in text: [1]
  13. Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998, 63, 9139–9144. doi:10.1021/jo9808526
    Return to citation in text: [1]
  14. Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69, 2362–2366. doi:10.1021/jo0352833
    Return to citation in text: [1]
  15. Ploypradith, P.; Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005, 70, 5119–5125. doi:10.1021/jo050388m
    Return to citation in text: [1]
  16. Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. J. Org. Chem. 2009, 74, 8143–8153. doi:10.1021/jo901589e
    Return to citation in text: [1]
  17. Gupton, J. T.; Clough, S. C.; Miller, R. B.; Lukens, J. R.; Henry, C. A.; Kanters, R. P. F.; Sikorski, J. A. Tetrahedron 2003, 59, 207–215. doi:10.1016/S0040-4020(02)01475-8
    Return to citation in text: [1]
  18. Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron 2006, 62, 594–604. doi:10.1016/j.tet.2005.10.014
    Return to citation in text: [1]
  19. Chen, L.; Xu, M.-H. Adv. Synth. Catal. 2009, 351, 2005–2012. doi:10.1002/adsc.200900287
    Return to citation in text: [1]
  20. Yadav, J. S.; Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R. Synlett 2009, 43–46. doi:10.1055/s-0028-1087387
    Return to citation in text: [1]
  21. Najera, C.; Sansano, J. M. Curr. Org. Chem. 1998, 7, 1105–1150. doi:10.2174/1385272033486594
    Return to citation in text: [1]
  22. Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53, 5951–5962. doi:10.1016/S0040-4020(97)00287-1
    Return to citation in text: [1]
  23. Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R. Chem. Commun. 1997, 2259–2260. doi:10.1039/a705874h
    Return to citation in text: [1]
  24. Cironi, P.; Manzanares, I.; Albericio, F.; Álvarez, M. Org. Lett. 2003, 5, 2959–2962. doi:10.1021/ol0351192
    Return to citation in text: [1]
  25. Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N. D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440–9448. doi:10.1021/jo061810h
    Return to citation in text: [1]
  26. Grigg, R.; Heaney, F. J. Chem. Soc., Perkin Trans. 1 1989, 198–200. doi:10.1039/p19890000198
    Return to citation in text: [1]
  27. Su, S.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744–7745. doi:10.1021/ja072737v
    Return to citation in text: [1]
  28. Yu, C.; Zhang, Y.; Zhang, S.; Li, H.; Wang, W. Chem. Commun. 2011, 47, 1036–1038. doi:10.1039/c0cc03186k
    Return to citation in text: [1]
  29. Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171–7175. doi:10.1002/anie.201102306
    Return to citation in text: [1] [2]
  30. Huang, L.; Zhao, J. Chem. Commun. 2013, 49, 3751–3753. doi:10.1039/c3cc41494a
    Return to citation in text: [1] [2]
  31. Guo, S.; Zhang, H.; Huang, L.; Guo, Z.; Xiong, G.; Zhao, J. Chem. Commun. 2013, 49, 8689–8691. doi:10.1039/c3cc44486d
    Return to citation in text: [1] [2]
  32. Wang, H.-T.; Lu, C.-D. Tetrahedron Lett. 2013, 54, 3015–3018. doi:10.1016/j.tetlet.2013.04.004
    Return to citation in text: [1]
  33. Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785–9789. doi:10.1002/anie.200904056
    Return to citation in text: [1]
  34. Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527–532. doi:10.1038/nchem.687
    Return to citation in text: [1]
  35. Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102–113. doi:10.1039/b913880n
    Return to citation in text: [1]
  36. Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828–6838. doi:10.1002/anie.201200223
    Return to citation in text: [1]
  37. Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687–7697. doi:10.1039/c2cs35203f
    Return to citation in text: [1]
  38. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322–5363. doi:10.1021/cr300503r
    Return to citation in text: [1]
  39. Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem. 2013, 9, 1977–2001. doi:10.3762/bjoc.9.234
    Return to citation in text: [1]
  40. Ravelli, D.; Fagnoni, M. ChemCatChem 2012, 4, 169–171. doi:10.1002/cctc.201100363
    Return to citation in text: [1] [2]
  41. Ravelli, D.; Fagnoni, M.; Albini, A. Chem. Soc. Rev. 2013, 42, 97–113. doi:10.1039/c2cs35250h
    Return to citation in text: [1] [2]
  42. Nicewicz, D. C.; Nguyen, T. M. ACS Catal. 2014, 4, 355–360. doi:10.1021/cs400956a
    Return to citation in text: [1] [2]
  43. Liu, H.; Feng, W.; Kee, C. W.; Zhao, Y.; Leow, D.; Pan, Y.; Tan, C.-H. Green Chem. 2010, 12, 953–956. doi:10.1039/b924609f
    Return to citation in text: [1]
  44. Pan, Y.; Kee, C. W.; Chen, L.; Tan, C.-H. Green Chem. 2011, 13, 2682–2685. doi:10.1039/c1gc15489c
    Return to citation in text: [1]
  45. Pan, Y.; Wang, S.; Kee, C. W.; Dubuisson, E.; Yang, Y.; Loh, K. P.; Tan, C.-H. Green Chem. 2011, 13, 3341–3344. doi:10.1039/c1gc15865a
    Return to citation in text: [1]
  46. Neumann, M.; Füldner, S.; König, B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50, 951–954. doi:10.1002/anie.201002992
    Return to citation in text: [1]
  47. Hari, D. P.; König, B. Org. Lett. 2011, 13, 3852–3855. doi:10.1021/ol201376v
    Return to citation in text: [1]
  48. Liu, Q.; Li, Y.-N.; Zhang, H.-H.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Chem.–Eur. J. 2012, 18, 620–627. doi:10.1002/chem.201102299
    Return to citation in text: [1]
  49. Fidaly, K.; Ceballos, C.; Falguières, A.; Veitia, M. S.-I.; Guy, A.; Ferroud, C. Green Chem. 2012, 14, 1293–1297. doi:10.1039/c2gc35118h
    Return to citation in text: [1]
  50. Fu, W.; Guo, W.; Zou, G.; Xu, C. J. Fluorine Chem. 2012, 140, 88–94. doi:10.1016/j.jfluchem.2012.05.009
    Return to citation in text: [1]
  51. Hari, D. P.; Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134, 2958–2961. doi:10.1021/ja212099r
    Return to citation in text: [1]
  52. Hari, D. P.; Hering, T.; König, B. Org. Lett. 2012, 14, 5334–5337. doi:10.1021/ol302517n
    Return to citation in text: [1]
  53. Neumann, M.; Zeitler, K. Org. Lett. 2012, 14, 2658–2661. doi:10.1021/ol3005529
    Return to citation in text: [1]
  54. Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134, 18577–18580. doi:10.1021/ja309635w
    Return to citation in text: [1]
  55. Rueping, M.; Vila, C.; Bootwicha, T. ACS Catal. 2013, 3, 1676–1680. doi:10.1021/cs400350j
    Return to citation in text: [1]
  56. Grandjean, J.; Nicewicz, D. A. Angew. Chem., Int. Ed. 2013, 52, 3967–3971. doi:10.1002/anie.201210111
    Return to citation in text: [1]
  57. Riener, M.; Nicewicz, D. A. Chem. Sci. 2013, 4, 2625–2629. doi:10.1039/c3sc50643f
    Return to citation in text: [1]
  58. Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Chem. Sci. 2013, 4, 3160–3165. doi:10.1039/c3sc51209f
    Return to citation in text: [1]
  59. Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588–9591. doi:10.1021/ja4031616
    Return to citation in text: [1]
  60. Perkowski, A. J.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 10334–10337. doi:10.1021/ja4057294
    Return to citation in text: [1]
  61. Pitre, S. P.; McTiernan, C. D.; Ismaili, H.; Scaiano, J. C. J. Am. Chem. Soc. 2013, 135, 13286–13289. doi:10.1021/ja406311g
    Return to citation in text: [1]
  62. Rueping, M.; Vila, C.; Koenings, R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47, 2360–2362. doi:10.1039/c0cc04539j
    Return to citation in text: [1]
  63. Rueping, M.; Zhu, S.; Koenings, R. M. Chem. Commun. 2011, 47, 8679–8681. doi:10.1039/c1cc12907d
    Return to citation in text: [1]
  64. Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011, 47, 9615–9617. doi:10.1039/c1cc13660g
    Return to citation in text: [1]
  65. Rueping, M.; Zhu, S.; Koenings, R. M. Chem. Commun. 2011, 47, 12709–12711. doi:10.1039/c1cc15643h
    Return to citation in text: [1]
  66. Rueping, M.; Zoller, J.; Fabry, D. C.; Poscharny, K.; Koenings, R. M.; Weirich, T. E.; Mayer, J. Chem.–Eur. J. 2012, 18, 3478–3481. doi:10.1002/chem.201103242
    Return to citation in text: [1]
  67. Rueping, M.; Koenings, R. M.; Poscharny, K.; Fabry, D. C.; Leonori, D.; Vila, C. Chem.–Eur. J. 2012, 18, 5170–5174. doi:10.1002/chem.201200050
    Return to citation in text: [1]
  68. Rueping, M.; Vila, C.; Szadkowska, A.; Koenigs, R. M.; Fronert, J. ACS Catal. 2012, 2, 2810–2815. doi:10.1021/cs300604k
    Return to citation in text: [1]
  69. Zhu, S.; Rueping, M. Chem. Commun. 2012, 48, 11960–11962. doi:10.1039/c2cc36995h
    Return to citation in text: [1]
  70. Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823–1829. doi:10.1021/ja309580a
    Return to citation in text: [1]
  71. Rueping, M.; Vila, C. Org. Lett. 2013, 15, 2092–2095. doi:10.1021/ol400317v
    Return to citation in text: [1]
  72. Vila, C.; Rueping, M. Green Chem. 2013, 15, 2056–2059. doi:10.1039/c3gc40587g
    Return to citation in text: [1]
  73. Tóth, J.; Váradi, L.; Dancsó, A.; Blaskó, G.; Töke, L.; Nyerges, M. Synlett 2007, 1259–1263. doi:10.1055/s-2007-977461
    Return to citation in text: [1]

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