Fluorene-Based Multicomponent Reactions

Xiaofang Lei; Maria Thomaidi; Giasemi K. Angeli; Alexander Dömling; Constantinos G. Neochoritis

doi:10.1055/a-1471-9080

Synlett, Table of Contents

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

^aDepartment of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece

^bDepartment of Pharmacy, Drug Design Group, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands

,

Maria Thomaidi

^aDepartment of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece

,

Giasemi K. Angeli

^aDepartment of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece

,

Alexander Dömling ∗

^bDepartment of Pharmacy, Drug Design Group, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands

,

Constantinos G. Neochoritis ∗

^aDepartment of Chemistry, University of Crete, Voutes, 70013, Heraklion, Greece

› Author Affiliations

Abstract

All articles of this category

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

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References

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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.

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