Syntheses of Oxazolidinone-2,3-Fused Indoline and Azaindoline Derivatives

Abstract

We herein describe a practical synthetic method to access oxazolidinone-2,3-fused indoline and azaindoline derivatives via one-pot cyclization. These derivatives, which contain sp³-hybridized carbons, may be useful as new scaffolds in medicinal chemistry.

Key words

3-bromo-2-hydroxy-1-tosylindoline - 3-bromo-2-hydroxy-1-tosylazaindoline - oxazolidinone - isocyanate - cyclization

Publication History

Received: 23 February 2023

Accepted after revision: 08 March 2023

Article published online:
05 April 2023

• References and Notes

• 1a Mérour J.-Y, Buron F, Plé K, Bonnet P, Routier S. Molecules 2014; 19: 19935
• 1b Motati DR, Amaradhi R, Ganesh T. Bioorg. Med. Chem. 2020; 28: 115830
• 1c Han Y, Dong W, Guo Q, Li X, Huang L. Eur. J. Med. Chem. 2020; 203: 112506
• 2a Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2014; 57: 5845
• 2b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 2c Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383
• 3a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 3b Lovering F. MedChemComm 2013; 4: 515
• 4 Nishi T, Mishima N, Kato H, Yamada K. Synlett 2021; 32: 1034
• 5 Benkovics T, Guzei IA, Yoon TP. Angew. Chem. Int. Ed. 2010; 49: 9153
• 6 Yamada K, Mishima N, Saito K, Nishi T. Tetrahedron 2021; 97: 132404
• 7 Yamada K, Ohta M, Kitamura G, Tsutsumiguchi S, Nishi T. Tetrahedron 2023; in press
• 8 CCDC 2234660 (1b) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 9 Krishnakumar KS, Goudedranche S, Bouch D, Strazewski P. J. Org. Chem. 2011; 76: 2253
• 10 Jia S, Tian Y, Li X, Wang P, Lan Y, Yan H. Angew. Chem. Int. Ed. 2022; 61: e202206501
• 11 Abe T, Suzuki T, Anada M, Matsunaga S, Yamada K, Yamada K. Org. Lett. 2017; 19: 4275
• 12 (2R*,3S*)-3-Bromo-4-chloro-1-tosylindolin-2-ol (1a): Typical Procedure To a solution of 4-chloro-1-tosylindole (4a; 4.00 g, 13.1 mmol) and H₂O (2.35 mL, 131 mmol) in acetone (80 mL) was added NBS (2.56 g, 14.4 mmol). The reaction mixture was stirred at room temperature for 7 h. The solvent was removed in vacuo, and the residue was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO₄. The solvent was removed in vacuo, and the residue was purified by flash silica gel column chromatography (n-hexane/EtOAc = 8:1–2:1) to obtain 1a as a white solid (4.74 g, 90% yield); mp 116–118 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.75 (d, J = 8.6 Hz, 2 H), 7.48 (d, J = 8.6 Hz, 1 H), 7.27 (m, 1 H), 7.26 (d, J = 8.6 Hz, 2 H), 7.05 (d, J = 8.1 Hz, 1 H), 6.01 (s, 1 H), 5.04 (s, 1 H), 3.73 (brs, 1 H), 2.37 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 145.1, 141.3, 135.2, 132.4, 132.2, 130.0, 127.8, 127.3, 125.1, 113.3, 93.5, 47.1, 21.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₃BrClNNaO₃S: 423.9386, 425.9365, and 427.9336; found: 423.9405, 425.9366, and 427.9362. (3aR*,8bR*)-8-Chloro-1-phenyl-4-tosyl-1,3a,4,8b-tetrahydro-2H-oxazolo[5,4-b]indol-2-one (2a): Typical Procedure Compound 1a (4.00 g, 9.93 mmol) was heated with phenyl isocyanate (1.77 g, 14.9 mmol) and cesium carbonate (4.84 g, 14.9 mmol) in THF (200 mL) at 80 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO₄. The solvent was removed in vacuo and the residue was crystallized from MeOH to obtain 2a as a white solid (3.63 g, 83% yield); mp 210–212 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.30–7.39 (m, 3 H), 7.20–7.25 (m, 4 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 5.85 (d, J = 7.5 Hz, 1 H), 2.43 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 154.4, 145.4, 142.5, 136.2, 135.4, 132.4, 132.2, 130.3, 129.4, 128.3, 127.9, 127.3, 125.3, 124.7, 112.0, 88.1, 62.2, 21.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₇ClN₂NaO₄S: 463.0495 and 465.0466; found: 463.0492 and 465.0476.