Andrew Jordan & Ravi Pathak from Charnwood Discovery published a research poster on ‘Rapid Optimisation of a Buchwald-Hartwig Amination using Design of Experiments (DoE)’. They wanted to identify optimal conditions for the synthesis of building block 3 via Buchwald-Hartwig amination, and used a combination of rapid screening and DoE to achieve this.

Reaction Scheme

Mya 4 Charnwood

After conducting a literature review of potential reaction conditions, the Radleys Mya 4 Reaction Station was used for rapid screening of sixteen catalyst-base combinations for the reaction.

By using the Mya 4 reaction station a full suite of reaction data was generated, including the UPLC-MS analysis of all 16 reactions, within just 2 hours.

Catalyst Base screening results

As shown in the table, the results of the screening process showed that the use of K3PO4 with Xphos Pd G3 gave he highest conversion to product 3. In the pie charts, green indicates conversion to product as determined by ULC-MS and red indicates by-products and unreacted starting materials.

After solvent screening, to find a more safe and sustainable alternative to dioxane, the optimum conditions were identified as: Xphos Pd G3 (5 mol%), K3PO4 (3 eq.), tBuOH (0.4 M conc.), reflux, 2 h – 90% Product.

3D Surface Response

The reaction was then subjected to further optimisation using DoE software from Design Expert. Various key reaction parameters were used including catalyst loading, equivalents of base, temperature and concentration.

The results were used to build a surface response plot, which led to improvements in the yield of the reaction, as well as avoiding the potential for a ‘false optimum’ which can be encountered when only changing one parameter at a time.

The combination of rapid screening in the Mya 4 reaction station and DoE led to discovery of the optimum reaction conditions: Xphos Pd G3 (0.5 mol%), K3PO4 (3 eq.), tBuOH (0.36 M conc.), reflux, 1 h – 98% Product.

See the poster here.