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

Abstract

We describe a practical method for synthesizing heterocycle-2,3-fused indoline or azaindoline derivatives through haloetherification and cyclization. We applied this method in syntheses of six- to eight-membered heterocycle-2,3-fused indoline and azaindoline derivatives. These derivatives, which contain sp³-hybridized carbons, might be useful as new scaffolds in medicinal chemistry.

Key words

haloetherification - indolines - azaindolines - morpholines - oxazepines - oxazocines

• References and Notes

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• 23 tert-Butyl [2-({3-Bromo-1-tosyl-2,3-dihydro-1H-indol-2-yl}oxy)ethyl]carbamate (6a): Typical ProcedureNBS (4.92 g, 27.6 mmol) was added to a solution of 1-tosylindole (5a; 5.00 g, 18.4 mmol) and N-Boc-2-aminoethanol (1; 8.91 g, 55.3 mmol) in C₆H₅CF₃ (100 mL), and the mixture was stirred at r.t. for 4 h. The mixture was then diluted with brine and extracted with EtOAc. The organic layer was dried (MgSO₄) and concentrated in vacuo, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1 to 3:1)] to give a white solid; yield: 7.34 g (78%); mp 118–120 °C.¹H NMR (500 MHz, CDCl₃): δ = 7.66 (t, J = 8.6 Hz, 2 H), 7.33 (m, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.11 (m, 1 H), 5.66 (s, 1 H), 4.95 (s, 1 H), 4.76 (br s, 1 H), 3.99 (m, 1 H), 3.82 (m, 1 H), 3.39 (m, 1 H), 3.31 (m, 1 H), 2.33 (s, 3 H), 1.44 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 155.9, 144.7, 140.6, 135.1, 131.3, 130.7, 129.6, 127.7, 126.3, 125.5, 117.0, 98.8, 79.5, 67.9, 47.3, 40.2, 28.5, 21.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₇BrN₂NaO₅S: 533.0722 and 535.0701; found: 533.0703 and 535.0686.tert -Butyl (4a R* ,9b R* )-5-Tosyl-2,3,5,9b-tetrahydro[1,4]oxazino[2,3- b ]indole-1(4a H )-carboxylate (1a): Typical ProcedureCompound 6a (5.00 g, 9.78 mmol) was treated with Ag₂O (11.32 g, 48.8 mmol) in EtOAc (150 mL) at 80 °C for 4 h. The mixture was then cooled to r.t. and filtered through a Celite pad. The solvent was removed in vacuo, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1 to 3:1)] to give a white solid; yield: 3.37 g (80%); mp 197–199 °C. Byproduct 8a was also obtained as a white solid; yield: 406 mg (10%).¹H NMR (500 MHz, DMSO-d ₆): δ = 7.83 (m, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.24 (br s, 2 H), 6.93–7.06 (m, 2 H), 5.89 + 5.80 (both d, J = 5.2 Hz, total 1 H), 5.36 + 5.21 (both d, J = 5.2 Hz, total 1 H), 3.37–3.65 (m, 2 H), 3.48 + 3.38 (both m, total 1 H), 2.80 + 2.63 (both m, total 1 H), 2.47 + 2.32 (both s, total 3 H), 1.44 + 1.38 (both s, total 9 H). ¹³C NMR (125 MHz, DMSO-d ₆, 100 °C): δ = 155.0, 144.8, 140.8, 136.8, 130.3, 130.1, 129.5, 127.8, 124.6, 124.6, 114.2, 87.1, 80.8, 60.9, 54.2, 41.0, 28.6, 21.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₆N₂NaO₅S: 453.1460; found: 453.1451.