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Synlett 2022; 33(02): 155-160
DOI: 10.1055/a-1471-9080
letter
EuCheMS Organic Division Young Investigator Workshop

Fluorene-Based Multicomponent Reactions

Xiaofang Lei
a   Department of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece
b   Department of Pharmacy, Drug Design Group, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
,
Maria Thomaidi
a   Department of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece
,
Giasemi K. Angeli
a   Department of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece
,
Alexander Dömling  ∗
b   Department of Pharmacy, Drug Design Group, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
,
Constantinos G. Neochoritis  ∗
a   Department of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece
› Author AffiliationsThe research project was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the ‘2nd Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers’ (Project Number: 0911). X.L. acknowledges support from the China Scholarship Council. This project has received funding (to A.D.) from the European Lead Factory (IMI) under Grant Agreement 115489, the Qatar National Research Foundation (NPRP6-065-3-012), the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska­-Curie [ITN ‘Accelerated Early stage drug dIScovery’, Grant Agreement 675555; Cofunds ALERT (665250) and PROMINENT (754425)].
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Dedicated to Professor Ioulia Stephanidou-Stephanatou for her contributions to heterocyclic chemistry

Abstract

Fluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery. Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized. We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts.

Key words

fluorene - fluorenone - multicomponent reactions - Ugi reaction - isocyanofluorene - spiro compounds

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1471-9080.
  • Supporting Information


Publication History

Received: 03 March 2021

Accepted after revision: 31 March 2021

Accepted Manuscript online:
31 March 2021

Article published online:
03 May 2021

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  • 66 Ugi-Tetrazole Four-Component (UT-4CR) Synthesis of 7a–e and 2b; General Procedure The appropriate aniline (1.0 mmol), isocyanide (1.0 mmol), and trimethylsilyl azide (1.0 mmol) were added to a stirred solution of the appropriate aldehyde (1.0 mmol) in MeOH (1.0 mL) at rt, and the mixture was stirred vigorously for 1–2 h. Half the solvent was removed under reduced pressure and, if a solid residue appeared, it was collected by filtration and washed with Et2O. Alternatively, the solvent was removed under reduced pressure, and the residue was purified by column chromatography [silica gel, PE–EtOAc (1:1)]. N-{1-[1-(9H-Fluoren-9-yl)-1H-tetrazol-5-yl]cyclohexyl}-3,4,5-trimethoxyaniline (7c) Gray solid; yield: 427 mg (86%); mp 216–218 °C. 1H NMR (500 MHz, DMSO-d 6): δ = 7.94 (d, J = 7.6 Hz, 2 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.26 (s, 1 H), 7.12 (s, 2 H), 6.39 (s, 2 H), 5.72 (s, 2 H), 3.59 (s, 3 H), 3.47 (s, 6 H), 2.87 (s, 1 H), 2.61–2.58 (m, 2 H), 2.352–2.348 (m, 2 H), 1.80–1.69 (m, 5 H), 1.47–1.44 (m, 1 H). 13C NMR (126 MHz, DMSO-d 6): δ = 160.3, 153.6, 141.6, 141.5, 140.0, 129.7, 129.5, 128.0, 124.1, 120.8, 91.6, 61.9, 60.5, 55.5, 53.5, 45.5, 24.8, 20.9. MS (ESI): m/z [M + Na]+ calcd for C29H31N5NaO3: 520.23; found: 520.07.
  • 67 Oxazoles 12a–c; General Procedure K2CO3 (1.5 mmol) was added to a stirred solution of the appropriate aldehyde (1.0 mmol) and 9-isocyano-9H-fluorene (1; 1.0 mmol) in MeOH (3.0 mL) at rt, and the mixture was stirred vigorously for 1–5 h. The solvent was then removed under reduced pressure and the residue was collected by filtration and washed with Et2O. Alternatively, the solvent was removed under reduced pressure and the residue was purified by column chromatography [silica gel, PE–EtOAc (4:1)]. 5′-(2-Phenylethyl)spiro[fluorene-9,4′-[1,3]oxazole] (12c) White solid; yield: 276 mg (85%); mp 161–163 °C. 1H NMR (500 MHz, DMSO-d 6): δ = 7.89–7.83 (m, 2 H), 7.69 (s, 1 H), 7.43–7.27 (m, 6 H), 7.10–7.05 (m, 3 H), 6.76 (d, J = 6.9 Hz, 2 H), 4.68–4.65 (m, 1 H), 2.30–2.25 (m, 1 H), 2.13–2.07 (m, 1 H), 1.89–1.88 (m, 1 H), 1.32–1.28 (m, 1 H). 13C NMR (126 MHz, DMSO-d 6): δ = 158.2, 148.1, 143.5, 140.6, 140.0, 139.9, 129.0, 128.9, 128.23, 128.18, 128.0, 127.4, 126.0, 125.9, 124.5, 120.5, 120.2, 85.1, 80.6, 32.9, 31.5. MS (ESI): m/z [M + Na]+ calcd for C23H19NNaO: 348.14; found: 348.10.