TCI Practical Example: Buchwald-Hartwig Amination of Aryl Chlorides using a Palladium Catalyst and XPhos Ligand

We are going to introduce the Buchwald-Hartwig cross-coupling of aryl chloride utilizing Pd(dba)₂ as a catalyst, and XPhos ligand.

Used Chemicals

• 4-Chlorotoluene [C0297]
• Morpholine [M0465]
• Bis(dibenzylideneacetone)palladium(0) (=Pd(dba)₂) [B1374]
• 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (=XPhos) [D5038]
• Sodium tert-Butoxide [S0450]
• Toluene

Procedure

To a 2-necked flask was charged with bis(dibenzylideneacetone)palladium(0) (36 mg, 0.0633 mmol, 1.5 mol%), XPhos (60 mg, 0.127 mmol, 3.0 mol%), sodium tert-butoxide (811 mg, 8.44 mmol, 2.0 equiv.) and toluene (5 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 5 min. 4-chlorotoluene (0.5 mL, 4.22 mmol, 1.0 equiv.), and morpholine (0.55 mL, 6.33 mmol, 1.5 equiv.) were added in one portion. The resulting mixture was stirred at reflux for 6 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The organic layer was washed with water (10 mL), and brine (10 mL), dried with Na₂SO₄ (20 g) and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane : ethyl acetate = 9 : 1) to afford the corresponding compound 1 as an orange solid (700 mg, 94%).

Experimenter's Comments

Toluene was degassed by bubbling with nitrogen gas for 30 min.
The reaction mixture was monitored by GC.

Analytical Data

Compound 1

¹H NMR (400 MHz, CDCl₃); δ 7.10 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.11 (t, J = 4.8 Hz, 4H), 2.28 (s, 3H).

¹³C NMR (101 MHz, CDCl₃); δ 149.1, 129.7, 129.5, 116.0, 66.9, 49.9, 20.4.

Lead Reference

• Expanding Pd-Catalyzed C−N Bond-Forming Processes:  The First Amidation of Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions
  • H. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653.

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