Controlling Reactivity and Selectivity in the Mizoroki-Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands
Eric S. Isbrandt, Devon E. Chapple, Nguyen Thien Phuc Tu, Victoria Dimakos, Anne Marie M. Beardall, Paul D. Boyle, Christopher N. Rowley*, Johanna M. Blacquiere*, Stephen G. Newman*
*Carleton University, Ottawa; Western U, London; University of Ottawa, Ottawa, Canada,
Email: christopherrowley
cunet.carleton.ca, johanna.blacquiereuwo.ca,
stephen.newmanuottawa.ca
E. S. Isbrandt, D. E. Chapple, N. T. . Tu, V. Dimakos, A. M. M. Beardall, P. D. Boyle, C. N. Rowley, J. M. Blacquiere, S. G. Newman, J. Am. Chem. Soc., 2024, 146, 5650-5660.
DOI: 10.1021/jacs.3c14612
Abstract
Two structurally related 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligands enable the regiodivergent arylation of styrenes. By simply altering the phosphorus substituent from a phenyl to tert-butyl group, both the linear and branched Mizoroki-Heck products can be obtained in high regioisomeric ratios.
see article for more examples
proposed transition states
Details
The article discusses a high-throughput evaluation of the Mizoroki−Heck reaction using 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligands. The study found that P2N2 ligands are more broadly applicable than traditional ligands, offering high reactivity and selectivity across various substrates. Two structurally related P2N2 ligands were identified to enable regiodivergent arylation of styrenes, producing either linear or branched products by altering the phosphorus substituent. Experimental and computational studies revealed that the selectivity is influenced by the interaction between the ligand and the incoming olefin. The P-Ph ligand favors linear products due to π−π interactions, while the P-tBu ligand favors branched products due to steric hindrance. The study highlights the potential of P2N2 ligands in organic synthesis, demonstrating their ability to achieve high regioselectivity in Mizoroki−Heck reactions. The findings suggest that further exploration of P2N2 ligands could reveal new applications and establish them as valuable tools in synthetic chemistry. The research was supported by various Canadian institutions and computational resources were provided by Compute Canada.
General Procedure for Regioselective Mizoroki-Heck couplings with styrene
For linear selective coupling, PPh2NArCF32 Pd G3 was used and reactions were run at 100°C.
For branch selective coupling, PtBu2NArCF32 Pd G3 was used and reactions were run at 85°C.
P2N2 Pd G3 (0.04 equiv, 0.008 mmol) was added to a dry 8 mL screw-capped reaction vial equipped with a magnetic stir bar outside the glovebox along with any solid starting materials. The vial was shipped inside the glovebox and PhMe was added (2.00 mL) via syringe. TMP (2 equiv, 0.40 mmol), aryl triflate (0.20 mmol), and alkene (1.1 equiv, 0.22 mmol) were added using a weight-calibrated micropipette if liquid. The vial was capped, removed from the glovebox, and placed in a stirring (350 rpm) pre-heated mineral oil bath at the indicated reaction temperature. After stirring for 16 hours, the reaction vial was removed from the oil bath and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and a small aliquot was filtered through a silica plug for crude GC-FID analysis to determine ratio of regioisomers. The reaction mixture was purified by flash column chromatography with SiO2 to obtain pure compound in ≥19:1 rr (regiomeric ratio).
Note: While reactions were set up in the glovebox, P2N2 Pd G3 complexes were stored in a moisture-free desiccator and weighed outside the glovebox
Troubleshooting and general suggestions
Throughout our investigations into optimization and scope, deviations from the optimal conditions were sometimes found to be beneficial.
Low conversion. For some scope examples, particularly Lewis-basic heterocyclic triflates, increasing the catalyst loading from 4 mol% to 8 mol% was generally found to increase conversion. This change was not universally beneficial.
Low selectivity. For certain substrate pairings, 1,4-dioxane is a superior solvent system compared to PhMe with respect to selectivity and/or yield. Unfortunately, there were no apparent trends for predicting which solvent gave optimal selectivity. However, it was found that toluene was, on average, more consistently selective with a wider range of coupling partners compared to other solvents (including 1,4-dioxane). If low selectivity is observed for a particular coupling, we suggest trying 1,4-dioxane.
Quality of triflate. Most aryl triflates can be stored in the fridge (4 °C) for an extended period with no noticeable decomposition. However, some aryl triflates are unstable. For example, freshly preparing 2-pyridyl triflate was found to be particularly crucial in the coupling. Different reaction outcomes were observed between two batches of 2-pyridyl triflate. The first batch of 2-pyridyl triflate was a week old while the second batch of 2-pyridyl triflate that was >2 months old. Impurities resulting from the decomposition of the aryl triflate can fully shutdown both the linear and branched reactions
Key Words
ID: J48-Y2024
