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TCI Practical Example: Buchwald-Hartwig Amination Using Pd₂(dba)₃ and tBu₃P·HBF₄

We are proud to present the synthesis of 4-methoxytriphenylamine via Buchwald-Hartwig amination of 4-chloroanisole and diphenylamine by using Pd₂(dba)₃ and tBu₃P·HBF₄ as catalysts.

Used Chemicals

• 4-Chloroanisole [C0122]
• Diphenylamine
• Tris(dibenzylideneacetone)dipalladium(0) (= Pd₂(dba)₃) [T2184]
• Tri-tert-butylphosphonium Tetrafluoroborate (= tBu₃P·HBF₄) [T2584]
• Sodium tert-Butoxide (= NaOtBu) [S0450]
• Toluene

Procedure

Diphenylamine (5.01 g, 29.6 mmol, 1.0 eq.), 4-chloroanisole (4.48 g, 31.4 mmol, 1.05 eq.) and degassed toluene (150 mL) were added to a 3-necked 300 mL round bottom flask. Then, Pd₂(dba)₃ (0.287 g, 0.131 mmol, 1 mol%), tBu₃P·HBF₄ (0.198 g, 0.683 mmol, 2 mol%) and sodium tert-butoxide (6.34 g, 66.0 mmol, 2.2 eq.) were added and the reaction mixture was refluxed for 16 h under nitrogen atmosphere. After cooled to room temperature, the reaction was diluted with dichloromethane (300 mL). The suspension was filtered and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude and brown solid. The crude product was purified by silica-gel column chromatography (hexane:ethyl acetate = 99:1 - 8:1) to afford the light brown solid (7.0 g) containing 10 mol% of diphenylamine. Removal of the residual diphenylamine by recrystallization from hexane (55 mL) gave 4-methoxytriphenylamine as a white solid (5.26 g, 65 % yield).

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:10. Starting materials: Rf = 0.36 (diphenylamine), 0.59 (4-chloroanisole); target product: Rf = 0.46).

Analytical Data

4-Methoxytriphenylamine

¹H NMR (400 MHz, CDCl₃); δ 7.26-7.17 (m, 4H), 7.10-6.98 (m, 6H), 6.98-6.91 (m, 2H), 6.89-6.82 (m, 2H), 3.79 (s, 3H).

¹³C NMR (101 MHz, CDCl₃); δ 156.72, 148.56, 141.00, 129.39, 127.72, 123.12, 122.15, 115.05, 55.77.

Lead Reference

• Air-Stable Trialkylphosphonium Salts:  Simple, Practical, and Versatile Replacements for Air-Sensitive Trialkylphosphines. Applications in Stoichiometric and Catalytic Processes
• • M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295.
• An Air and Thermally Stable One- Component Catalyst for the Amination of Aryl Chlorides
• • D. Zim, S. L. Buchwald, Org. Lett. 2003, 5, 2413.

Other References

• A Simple Catalytic Method for the Conversion of Aryl Bromides to Arylamines
• • A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem. Int. Ed. 1995, 34, 1348.
• Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents
• • J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609.