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. 2021 Mar 31;23(8):3100–3104. doi: 10.1021/acs.orglett.1c00785

Synthesis of Carbazoles by a Diverted Bischler–Napieralski Cascade Reaction

Matteo Faltracco †, Said Ortega-Rosales †, Elwin Janssen †, Răzvan C Cioc ‡, Christophe M L Vande Velde §, Eelco Ruijter †,*
PMCID: PMC8056386  PMID: 33787266

Abstract

graphic file with name ol1c00785_0008.jpg

An unforeseen twist in a seemingly trivial Bischler–Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

Since its first report in 1893, the Bischler–Napieralski reaction has been widely employed for the synthesis of dihydro-β-carbolines and -isoquinolines owing to its robustness and broad functional group tolerance.1 Even currently, the Bischler–Napieralski reaction and its contemporary variations are still the object of intensive study in many areas, including natural product synthesis.2 In light of our interest in bioactive indole alkaloids and related compounds,3 we employed the Bischler–Napieralski reaction to access a series of dihydro-β-carbolines. However, when we subjected styrylacetamide 1a to typical Bischler–Napieralski conditions (POCl3, MeCN, reflux, 1 h) we serendipitously found near-quantitative formation of 3-phenylcarbazole (3a) instead of the expected dihydro-β-carboline 2a (Scheme 1A). The structure of 3a was confirmed by 1H and 13C NMR, HRMS, and X-ray crystallography.

Scheme 1. (A) Unexpected Carbazole Formation; (B) Bioactive Carbazoles.

Scheme 1

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Although carbazoles are less common than the related indoles among natural products and medicinal compounds, various carbazoles displaying interesting properties have been reported (Scheme 1B).4 Notable examples include the anticancer natural products staurosporine5 (and its clinically used semisynthetic derivative, midostaurin6) and ellipticine.7

Recently, carbazole derivative 4 was identified as a lead for new antitrypanosomiasis drugs,8 while glycozoline is known for its antibacterial, antifungal, antifeedant, and anti-inflammatory properties.9 Typical methods for the synthesis of carbazoles involve high temperature, long reaction times, and often metal catalysis (sometimes replaced by iodine or Lewis acids).10,11 Intrigued by our preliminary result, we decided to further explore the synthetic potential of this novel, mild, and metal-free route to carbazoles in more detail.

Puzzled by the surprising, but highly efficient formation of 3a, we set out to investigate the generality of the process. A series of diversely substituted tryptamides 1a–t was subjected to the reaction conditions (POCl3, MeCN, reflux, 1 h). Pleasingly, we observed that all substrates underwent full conversion within 1 h (Scheme 2). Both electron-withdrawing and electron-donating substituents on the indole (R2) are tolerated without significant influence on the yield, affording the corresponding products 3b–k in mostly good yield, with 5-fluoro substitution giving the lowest yield (3h, 49%). Similarly, N-alkyl substituents had very little effect on the reaction outcome (3d–k). The effect of varying R3 substitution is more significant. Electron-deficient arenes as R3 substituents perform best (3l, 3n, and especially 3p). In contrast, products bearing an electron-rich aryl (3m, 3o) or 3-thienyl R3 substituent (3q) were obtained in lower yields. Interestingly, esters as the R3 substituent were also able to promote the transformation, affording the corresponding carbazoles in high yield when the indole core is unsubstituted (3r,s, R1 = R2 = H) and in moderate yield when a 5-methoxy group is present (3t). Treatment of 3t with LiAlH4 afforded the natural product glycozoline (3u) which, together with 3s, has been isolated from Clausena lansium.12

Scheme 2. Scope of the Carbazole Formation.

Scheme 2

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All reactions were performed with 0.2 mmol of 1a–t, 0.3 mmol of POCl3, refluxing in MeCN for 1 h.

Performed on a 2 mmol scale.

Obtained by treatment of 2t with LiAlH4.

Once we established the generality of the reaction, we began our mechanistic investigation by the systematic variation of the substitution of the styrylacetic acid moiety in 1a (Scheme 3). Reaction of the γ-methyl-substituted styrylacetamide 1u led to a complex reaction mixture containing traces of the corresponding regular Bischler–Napieralski product, but no carbazole derivatives. Reaction of the β-methyl-substituted substrate 1v gave 2-methylcarbazole 3v, while α-methyl-substituted styrylacetamide 1w afforded 1-methylcarbazole 3w.

Scheme 3. Systematic Methyl Substitution.

Scheme 3

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These results may be rationalized by either transfer of the cinnamyl moiety to the indole C2 position or a complete rearrangement of the starting material involving ring opening of the indole moiety. The reaction of 1x, bearing a methyl substituent at the indole C2 position, surprisingly afforded 4-methyl-3-phenylcarbazole (3x). The formation of 3x can only be rationalized by a methyl migration or ring opening of the indole. Finally, we employed 13C-labeled substrate 1a*(13) and observed the incorporation of the 13C label at the 9a position of carbazole 3a*.

Based on the results summarized in Scheme 3 and relevant prior literature,14 we could postulate a mechanism to rationalize the formation of 3a from 1a (Scheme 4). Plausibly, the reaction is initiated by the formation of nitrilium ion 5, which undergoes attack by the indole C3 position to give spiroindolenine derivative 6. In the Bischler–Napieralski reaction, 6 undergoes a rapid Plancher rearrangement, leading to dihydro-β-carboline 2a after deprotonation of 7. In this case, however, the presence of the styryl moiety makes tautomerization to 8 more favorable. The resulting vinylogous enamine attacks the protonated indolenine, leading to formation of the tetracyclic scaffold 9. Then, β-elimination of the (protonated) aromatic amine takes place, opening up the indoline ring in 10. The resulting aniline 11 subsequently undergoes imine transfer (via the bridged aminal 12) to form the carbazole framework. The resulting dihydrocarbazole 13 finally undergoes attack by an unidentified nucleophile (most likely chloride) to give 3a with aromatization as a strong thermodynamic driving force.

Scheme 4. Postulated Mechanism.

Scheme 4

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Once we established a plausible mechanism, we realized that this complex, multistep transformation offers numerous opportunities for interruption or diversion of the reaction by judicious selection of substituents. First, we explored the possibility of diverting the cascade process by considering the equilibrium between 11, 12, and 13 that ultimately leads to the formation of 3a. We reasoned that the nucleophilic attack that takes place on the sp3 carbon of 13 could be avoided if the aliphatic linker is replaced by an aromatic one. Indeed, subjecting the phenylene-linked amide 1y to the cyclization conditions afforded carbazole 14 in 75% yield (Scheme 5). Based on the above-mentioned considerations, we expected that the cascade would proceed analogously to the formation of 3a until intermediate 17 and be interrupted at that stage. However, aromatization proved too great a driving force also in this case. As SN2 substitution is not possible in this case (cf. 13 to 3a, Scheme 4), the 1,2-aryl migration of the aniline fragment in 16 would re-establish the aromaticity of the system in the final stage. It is interesting to note that aminal intermediate 17 has an internal mirror plane and the two iminium species 16 and 16′ are identical, thus leading to the formation of a single carbazole product (14).

Scheme 5. Aromatic Linker Diversion.

Scheme 5

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Next, we focused our attention on intermediate 10 (Scheme 4), the tetracyclic core of which is present in a variety of natural products.15 To target this scaffold, ring opening of the indole (leading to 11, Scheme 4) needs to be prevented. Thus, we synthesized C2 Br-substituted styrylacetamide 18a to offer an alternative elimination pathway, interrupting the cascade at this stage. Indeed, the reaction of 18a does undergo a diverted pathway; however, the product was again a carbazole (19a, Scheme 6), albeit with yet another surprising substitution pattern. The formation of 19a could be rationalized by an alternative evolution of intermediate 20. At this point, elimination of HBr is favored over indoline ring opening, leading to 21. Similarly to the conversion of 13 to 3a (Scheme 4), attack of a chloride anion would terminate the cascade to give carbazole 19a.

Scheme 6. C2 Bromide Diversion.

Scheme 6

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We then proceeded to demonstrate the generality of this alternative transformation (Scheme 7). All desired products 19a–f were obtained in moderate to very good yield, although we observed higher yields for products bearing electron-withdrawing substituents such as halogens and CF3 (19b, 19d, 19e), yet the highest yield was observed for the unsubstituted product 19a. In contrast, the presence of a methyl substituent led to a lower yield (19c), whereas replacing the phenyl ring with a thienyl moiety reduced the yield significantly (19f).

Scheme 7. Scope of C2 Bromide Diversion.

Scheme 7

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All reactions were performed with 0.2 mmol of 18a–f, 0.3 mmol of POCl3, refluxing in MeCN for 1 h.

In conclusion, we report the serendipitous discovery of a diverted Bischler–Napieralski cascade reaction yielding carbazoles. The method features metal-free conditions, good yields, and high functional group tolerance. Systematic experimentation allowed us to confidently establish a complex multistep reaction mechanism, which allowed for straightforward further diversion or interruption of the reaction pathway to give different carbazole regioisomers. Efforts to further exploit the tetracyclic intermediates in the reaction in the total synthesis of indole alkaloids are currently ongoing in our laboratory.

Acknowledgments

This work was financially supported by The Netherlands Organisation for Scientific Research (NWO).We thank Xander Schaapkens and Ad Ruigrok van de Werve for preliminary experiments and Daniël Preschel for HRMS measurements (all VUA). We thank the Hercules Foundation (Project AUGE/11/029 “3D-SPACE: 3D Structural Platform Aiming for Chemical Excellence”) for funding the diffractometer, and Prof. Kristof Van Hecke (University of Ghent) for making available diffractometer time.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c00785.

  • Experimental details and characterization data, 1H and 13C NMR spectra, 2D NMR spectra (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 1a–y, 3a–x, 14, 18a–f and 19a–f (ZIP)

Accession Codes

CCDC 2062984 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.

Supplementary Material

ol1c00785_si_001.pdf (11MB, pdf)
ol1c00785_si_002.zip (50.4MB, zip)

References

  1. Bischler A.; Napieralski B. Zur Kenntniss einer neuen Isochinolinsynthese. Ber. Dtsch. Chem. Ges. 1893, 26, 1903–1908. 10.1002/cber.189302602143. [DOI] [Google Scholar]
  2. a Wang S.; Si R.; Zhuang Q.; Guo X.; Ke T.; Zhang X.; Zhang F.; Tu Y. Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler–Napieralski/Semipinacol Rearrangement Reaction. Angew. Chem., Int. Ed. 2020, 59, 21954–21958. 10.1002/anie.202009238. [DOI] [PubMed] [Google Scholar]; b Magnus P.; Payne A. H.; Hobson L. Synthesis of the Kopsia alkaloids (±)-11,12-demethoxylahadinine B, (±)-kopsidasine and (±)-kopsidasine-N-oxide. Tetrahedron Lett. 2000, 41, 2077–2081. 10.1016/S0040-4039(00)00118-0. [DOI] [Google Scholar]; c Mewald M.; Medley J. W.; Movassaghi M. Concise and Enantioselective Total Synthesis of (−)-Mehranine, (−)-Methylenebismehranine, and Related Aspidosperma Alkaloids. Angew. Chem., Int. Ed. 2014, 53, 11634–11639. 10.1002/anie.201405609. [DOI] [PMC free article] [PubMed] [Google Scholar]; d White K. L.; Movassaghi M. Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives. J. Am. Chem. Soc. 2016, 138, 11383–11389. 10.1021/jacs.6b07623. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Kang T.; White K. L.; Mann T. J.; Hoveyda A. H.; Movassaghi M. Enantioselective Total Synthesis of (−)-Deoxoapodine. Angew. Chem., Int. Ed. 2017, 56, 13857–13860. 10.1002/anie.201708088. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Magnus P.; Gazzard L.; Hobson L.; Payne A. H.; Lynch V. Studies on the synthesis of the indole alkaloids pauciflorine A and B. Tetrahedron Lett. 1999, 40, 5135–5138. 10.1016/S0040-4039(99)00882-5. [DOI] [Google Scholar]
  3. a de Graaff C.; Bensch L.; Boersma S. J.; Cioc R. C.; van Lint M. J.; Janssen E.; Turner N. J.; Orru R. V. A.; Ruijter E. Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction. Angew. Chem., Int. Ed. 2015, 54, 14133–14136. 10.1002/anie.201507041. [DOI] [PubMed] [Google Scholar]; b Saya J. M.; van Wordragen E. D. H.; Orru R. V. A.; Ruijter E. Mild and Practical Indole C2 Allylation by Allylboration of in situ Generated 3-Chloroindolenines. Eur. J. Org. Chem. 2019, 2019, 5156–5160. 10.1002/ejoc.201801745. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Saya J. M.; Roose T. R.; Peek J. J.; Weijers B.; de Waal T. J. S.; Vande Velde C. M. L.; Orru R. V. A.; Ruijter E. Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine. Angew. Chem., Int. Ed. 2018, 57, 15232–15236. 10.1002/anie.201809678. [DOI] [PubMed] [Google Scholar]
  4. For reviews, see:; a Schmidt A. W.; Reddy K. R.; Knölker H.-J. Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193–3328. 10.1021/cr200447s. [DOI] [PubMed] [Google Scholar]; b Bauer I.; Knölker H.-J. Synthesis of pyrrole and carbazole alkaloids. Top. Curr. Chem. 2011, 309, 203–253. 10.1007/128_2011_192. [DOI] [PubMed] [Google Scholar]
  5. Stepczynska A.; Lauber K.; Engels I. H.; Janssen O.; Kabelitz D.; Wesselborg S.; Schulze-Osthoff K. Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation. Oncogene 2001, 20, 1193–1202. 10.1038/sj.onc.1204221. [DOI] [PubMed] [Google Scholar]
  6. Hsiao S.-H.; Lusvarghi S.; Huang Y.-H.; Ambudkar S. V.; Hsu S.-C.; Wu C.-P. The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents. Cancer Lett. 2019, 445, 34–44. 10.1016/j.canlet.2019.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Auclair C. Multimodal action of antitumor agents on DNA: The ellipticine series Arch. Arch. Biochem. Biophys. 1987, 259, 1–14. 10.1016/0003-9861(87)90463-2. [DOI] [PubMed] [Google Scholar]
  8. Thomas S. M.; Purmal A.; Pollastri M.; Mensa-Wilmot K. Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis. Sci. Rep. 2016, 6, 32083. 10.1038/srep32083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. a Momin A. A.; Urmode T. D.; Bhosale S. M.; Kusurkar R. S. Short synthesis of carbazole alkaloids: Ekeberginine, murrayaquinone A, and glycozoline. Synth. Commun. 2016, 46, 1292–1298. 10.1080/00397911.2016.1192652. [DOI] [Google Scholar]; b Forke R.; Krahl M. P.; Krause T.; Schlechtingen G.; Knölker H.-J. Transition Metals in Organic Synthesis, Part 82. First Total Synthesis of Methyl 6-Methoxycarbazole-3-carboxylate, Glycomaurrol, the Anti-TB Active Micromeline, and the Furo[2,3-c]carbazole Alkaloid Eustifoline-D. Synlett 2007, 2007, 268–272. 10.1055/s-2007-967984. [DOI] [Google Scholar]
  10. a Tian X.; Song L.; Hashmi A. S. K. Synthesis of Carbazoles and Related Heterocycles from Sulfilimines by Intramolecular C–H Aminations. Angew. Chem., Int. Ed. 2020, 59, 12342–12346. 10.1002/anie.202000146. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Reddy C. R.; Subbarao M.; Sathish P.; Kolgave D. H.; Donthiri R. R. One-Pot Assembly of 3-Hydroxycarbazoles via Uninterrupted Propargylation/Hydroxylative Benzannulation Reactions. Org. Lett. 2020, 22, 689–693. 10.1021/acs.orglett.9b04472. [DOI] [PubMed] [Google Scholar]; c Chen S.; Li Y.; Ni P.; Huang H.; Deng G. J. Indole-to-Carbazole Strategy for the Synthesis of Substituted Carbazoles under Metal-Free Conditions. Org. Lett. 2016, 18, 5384–5387. 10.1021/acs.orglett.6b02762. [DOI] [PubMed] [Google Scholar]; d Guo T.; Han L.; Wang T.; Lei L.; Zhang J.; Xu D. Copper-Catalyzed Three-Component Formal [3 + 1 + 2] Benzannulation for Carbazole and Indole Synthesis. J. Org. Chem. 2020, 85, 9117–9128. 10.1021/acs.joc.0c01056. [DOI] [PubMed] [Google Scholar]; e Kundu S.; Banerjee A.; Maji M. S. Brønsted Acid-Catalyzed Tandem Pinacol-Type Rearrangement for the Synthesis of α-(3-Indolyl) Ketones by Using α-Hydroxy Aldehydes. J. Org. Chem. 2019, 84, 16003–16012. 10.1021/acs.joc.9b02474. [DOI] [PubMed] [Google Scholar]; f Aggarwal T.; Sushmita; Verma A. K. Recent advances in the synthesis of carbazoles from indoles. Org. Biomol. Chem. 2019, 17, 8330–8342. 10.1039/C9OB01381D. [DOI] [PubMed] [Google Scholar]
  11. For an elegant, metal-free carbazole annulation cascade starting from indoles, see:; Stepherson J. R.; Ayala C. E.; Tugwell T. H.; Henry J. L.; Fronczek F. R.; Kartika R. Carbazole Annulation via Cascade Nucleophilic Addition–Cyclization Involving 2-(Silyloxy)pentadienyl Cation. Org. Lett. 2016, 18, 3002–3005. 10.1021/acs.orglett.6b01376. [DOI] [PubMed] [Google Scholar]
  12. a Deng H.-D.; Mei W.-L.; Wang H.; Guo Z.-K.; Dong W.-H.; Wang H.; Li S.-P.; Dai H.-F. Carbazole alkaloids from the peels of Clausena lansium. J. Asian Nat. Prod. Res. 2014, 16, 1024–1028. 10.1080/10286020.2014.930442. [DOI] [PubMed] [Google Scholar]; Glycolizine has also been isolated from various other plant sources; for a review, see:; b Knölker H.-J.; Reddy K. R. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303–4427. 10.1021/cr020059j. [DOI] [PubMed] [Google Scholar]
  13. The 13C-labeled substrate 4a* was readily prepared by Pd-catalyzed carbonylation of cinnamyl alcohol using [13C]-formic acid. See:Fu M.-C.; Shang R.; Cheng W.-M.; Fu Y. Efficient Pd-Catalyzed Regio- and Stereoselective Carboxylation of Allylic Alcohols with Formic Acid. Chem. - Eur. J. 2017, 23, 8818–8822. 10.1002/chem.201701971. [DOI] [PubMed] [Google Scholar]
  14. For an earlier example of a diverted Bischler–Napieralski reaction involving indole ring opening, see:Frost J. R.; Gaudillière B. R. P.; Kauffmann E.; Loyaux; Normand N.; Petry G.; Poirier P.; Wenkert E.; Wick A. E. Intermolecular Trapping by Indole of a Spiroindolenine Intermediated Formed during the Bischler–Napieralski Cyclisation of N-Acetyltryptamine. Heterocycles 1989, 28, 175–182. 10.3987/COM-88-S90. [DOI] [Google Scholar]
  15. Saya J. M.; Ruijter E.; Orru R. V. A. Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization. Chem. - Eur. J. 2019, 25, 8916–893. 10.1002/chem.201901130. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

ol1c00785_si_001.pdf (11MB, pdf)
ol1c00785_si_002.zip (50.4MB, zip)

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