Scale-Up Guide: Buchwald-Hartwig Amination Reaction

Kit to Hit Scale-Up Guide

KitAlysis header

Important Note

All of the preformed catalysts used in the kit are air and moisture stable complexes in their commercially available form. Once activated by base under the reaction conditions they become sensitive to air. To best enable scale-up success, the use of standard Schlenk technique is recommended.

General Guidelines for Catalytic Reaction Scale-Up

  • Oven dry all glassware and stir bars
  • Preheat oil bath to avoid temperature spiking
  • Use dry, high purity reagents (and substrates)1
  • Use unopened Sure/Seal™ anhydrous solvents (or newly degassed)1
  • Keep reactions under an atmosphere of nitrogen

Example Experimental

All solids (base, substrates, catalyst) were weighed on a bench top balance and added to a cooled, oven dried flask1,2 equipped with an oven dried stir bar. The reaction was capped and then purged and backfilled with nitrogen (3x) with a nitrogen-fed manifold needle. Anhydrous solvent (SureSeal™ed and punctured with a nitrogen-fed manifold needle) was then added via syringe.  If a liquid bases was required, it was added as the final component via syringe. When all constituents were added, the nitrogen line was removed3 and the reaction allowed to stir at the required temperature for the duration of the reaction.

1See the Cross-Coupling Reaction Manual: Desk Reference and Cross-Coupling Quick Guide: Bench Reference for more detailed additional guidance and troubleshooting tips

2Reaction vials capable of being sealed with a microwave cap are very useful as well. By design, the caps do not need to be replaced once punctured.

3For higher temps, a reflux condenser operated under nitrogen can be used

Buchwald-Hartwig Amination Reaction Product List

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Description Product No. Vial
BrettPhos Pd G3 761605 A1, C1
CPhos Pd G3 763004 A2, C2
DavePhos Pd G3 804959 A3, C3
P(tBu3) Pd G2 756482 A4, C4
J009 Pd G3 747130 A5, C5
MorDalPhos Pd G3 792357 A6, C6
BINAP Pd G3 804967 B1, D1
RuPhos Pd G2 753246 B2, D2
SPhos Pd G2 753009 B3, D3
tBuXPhos Pd G3 762229 B4, D4
XantPhos Pd G3 763039 B5, D5
XPhos Pd G3 763381 B6, D6

Other materials to be noted:

Sure/Seal™ solvents and bases Product No.
dioxane 296309
DMAc 271012
NaOtBu (2 M in THF) 702706
cesium carbonate 202126