I am conducting a synthesis involving Buchwald–Hartwig amination. Catalyst is $\ce{Pd2(dba)3},$ ligand is $\ce{P(o-tol)3},$ base is $\ce{Et3N},$ and solvent is toluene. Image below is the proposed mechanism.

Buchwald–Hartwig cross-coupling catalytic cycle

I used $\ce{Et3N}$ as base, so I assume that an ionic compound $\ce{(Et3NH)+Br-}$ is formed. Should I do solvent extraction with water to remove triethylamine hydrobromide?

I couldn't find any procedures in the literature, although some papers mention Celite filtration.

  • 3
    $\begingroup$ The triethylamine hydrobromide is not toluene soluble so it should be removed by the Celite filtration $\endgroup$
    – Waylander
    Jul 22 at 8:16
  • 2
    $\begingroup$ Ah, I just forgot that they would not be soluble in toluene so be precipitated. Thank you! $\endgroup$
    – Krang Lee
    Jul 22 at 8:18

It seems like you figured out that filtration of the reaction mixute through a Celite$^®$ pad would work in this case since you have used nonpolar solvent such as toluene. However, if you have used tert-butoxide (e.g., $\ce{KOC(CH3)3}$) insteard as in the given mechanism, the byproduct is tert-butanol, which is soluble in toluene. In this case, you can do solvent-sovent extraction to remove most of byproducts.

The workup procedures in Buchwald–Hartwig amination reaction is depends on the type of base and the solvent used. For example, see following two examples:

Reaction for example 1

  1. A mixture of 2,6-dichloropyrazine (25 g, 168 mmol), 4-((3-methyloxetan-3- yl)methoxy)-2-nitrobenzenamine (40 g, 168 mmol), palladium (II) acetate (1.5 g, 6.72 mmol), (±)-2,2-bis(diphenylphosphino)-1,1'-binaphinyl [(±)-BINAP] (4.18 g, 6.72 mmol), and cesium carbonate (76.7 g, 235.2 mmol) in toluene (800 mL) was stirred at $\pu{90 ^\circ C}$ under $\ce{N2}$ for 23 h. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica (EtOAc : petroleum ether = 1:5) which gave the title compound as a red solid (22.4 g, 37% yield) (Pfizer Patent: WO2010016005).

Reaction for example 2

  1. A mixture of (6-bromo-4H-benzo[d][l,3]oxazin-2-yl)-(R)-indan-l-yl-amine (172 mg, 0.5 mmol), commercially available 2-amino-6-trifiuoromethyl-pyridine (162 mg, 1.0 mmol), tert-Bu-XPhos (34 mg, 0.08 mmol), $\ce{Pd2dba3}$ (18 mg, 0.02 mmol), sodium tert-butylate (53 mg, 0.55 mmol), tert-butanol (0.5 ml) and dioxane (3 ml) was heated in a sealed tube at $\pu{120 ^\circ C}$ for 16 h. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (magnesium sulfate) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/ heptane) yielded the title compound (127 mg, 60%) as light brown foam (Roche Patent: WO2010026110).

I used toluene as solvent. Ionic compound Et3NHBr (although it's unclear that it is really formed) is insoluble in organic solvent such as toluene, so it can be filtrated through Celite pad.


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