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TCI Practical Example: Goldberg Amination Using Capsule Reagents

We are proud to present Goldberg amination using capsule reagents. Capsule reagents can omit weighing the catalyst and ligand. Each capsule includes 200 μmol of 1,10-phenanthroline and 800 μmol of copper(I) iodide, respectively.

Used Chemicals

• 2-Bromopyridine [B0650]
• Indole [I0021]
• Cesium Carbonate [C2160]
• Cupper(I) Iodide (HPMC encapsulated) [R0314]
• 1,10-Phenanthroline (HPMC encapsulated) [R0309]
• DMSO

Procedure

Copper(I) iodide (HPMC encapsulated) (one capsule) and 1,10-phenanthroline (HPMC encapsulated) (one capsule) were added to a solution of indole (93.7 mg, 800 µmol), 2-bromopyridine (164 mg, 1.04 mmol, 1.3 eq.) and cesium carbonate (521 mg, 1.60 mmol, 2.0 eq.) in DMSO (2.5 mL) at room temperature. The reaction mixture was stirred at 150 °C for 2 hours. After cooling to room temperature, the solution was diluted with ethyl acetate (15 mL) and sat. Na₂SO₄ aq. (15 mL), and filtered through Celite pad. The filtrate was extracted with ethyl acetate (15 mL x 2). The organic layer was washed with 2 mol/L HCl (15 mL) and sat. NaHCO₃ aq. (15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 - 5:1) to afford N-(2-pyridyl)indole (130 mg, 84% yield) as a pale-yellow oil.

Experimenter's Comments

The reaction mixture was monitored by UPLC.
The material of the capsule is water-soluble HPMC (hydroxypropyl methylcellulose).
The capsule has the shape shown in Figure 1 and 1,10-phenanthroline (ca. 200 μmol) and copper(I) iodide (ca. 800 μmol) are encapsulated in each capsule, respectively.
The capsules dissolves in water or polar solvents as shown in Figure 2.

 

Analytical Data

N-(2-Pyridyl)-indole

¹H NMR (400 MHz, CDCl₃); δ 8.21 (d, 1H, J = 8.0 Hz), 7.85-7.81 (m, 1H), 7.37 (d, 1H, J = 4.0 Hz), 7.67 (d, 1H, J = 8.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.30(t, 1H, J = 8.0 Hz), 7.23-7.16 (m, 2H).

Lead Reference

• Reagent and Catalyst Capsules: A Chemical Delivery System for Reaction Screening and Parallel Synthesis
  • N. Borlinghaus, B. Schönfeld, S, Heitz, J. Klee, S. Vukelić, W. M. Braje, A. Jolit, J. Org. Chem. 2021, 86, 1357.

Other References

• Transition-Metal-Free O-, S-, and N-Arylation of Alcohols, Thiols, Amides, Amines, and Related Heterocycles
  • R. Cano, D. J. Ramon, M. Yus, J. Org. Chem. 2011, 7, 654.