Design and Application of a Screening Set for Monophosphine Ligands in Cross-Coupling

Abstract

In reaction discovery, the search space of discrete reaction parameters such as catalyst structure is often not explored systematically. We have developed a tool set to aid the search of optimal catalysts in the context of phosphine ligands. A virtual library, kraken, which is representative of the monodentate P­(III)-ligand chemical space, was utilized as the basis to represent the discrete ligands as continuous variables. Using dimensionality reduction and clustering techniques, we suggested a Phosphine Optimization Screening Set (PHOSS) of 32 commercially available ligands that samples this chemical space completely and evenly. We present the application of this screening set in the identification of active catalysts for various cross-coupling reactions and show how well-distributed sampling of the chemical space facilitates identification of active catalysts. Furthermore, we demonstrate how proximity in ligand space can be a useful guide to further explore ligands when very few active catalysts are known.

Emerging Trends in Cross-Coupling: Twelve-Electron-Based L1Pd(0) Catalysts, Their Mechanism of Action, and Selected Applications

“…Ligand parametrization for predicting the outcome of a catalytic reaction with the help of data science is emerging as a new tool in organic synthesis. − Although the Tolman cone angle , descriptor has been of great value in understanding and predicting ligand properties in catalysis, it suffers from certain drawbacks, one of which is not taking ligand flexibility into consideration. − Recently, the groups of Sigman and Doyle reported that the use of a single descriptor, minimum percent buried volume or % V bur (min), could nicely predict the ligation state of the catalytically active complexes in both Pd- and Ni-catalyzed reactions . Initially, the authors were inspired by the high efficiency of the DinoPhos ligand family (TyrannoPhos and TriceraPhos) in the Ni-catalyzed coupling reaction of acetal and boroxine (Scheme ).…”

Data-Driven Multi-Objective Optimization Tactics for Catalytic Asymmetric Reactions Using Bisphosphine Ligands

“…As showcased below, the designer maps can be applied to various downstream data science steps in multi-objective optimization campaigns. In addition to the reaction optimization applications presented (vide infra), it can be envisioned that this calculated parameter library and chemical space map could be used for many other potential applications such as training set design, novel ligand generation, and mechanistic understanding …”

Facile Assembly of Modular-Type Phosphines for Tackling Modern Arylation Processes

“…Remarkably, heteroaryl tosylate coupling at room temperature without any reduction in the product yield was also demonstrated. Recently, Sigman used the Pd 2 (dba) 3 / CM-phos catalyst system for the SMC of aryl chlorides, aryl triflates, and sterically hindered aryl bromides …”

“…Recently, Sigman used the Pd 2 (dba) 3 /CM-phos catalyst system for the SMC of aryl chlorides, aryl triflates, and sterically hindered aryl bromides. 15 In addition to arylboronic acids, other boronic acid surrogates such as trifluoroborate salts and pinacol boronate esters were coupled smoothly with good yields. 13,14 The coupling of aryl mesylates with potassium (hetero)aryl-, alkyl-, and vinyl-trifluoroborate salts was also successfully accom-plished (Scheme 5B).…”