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The testing of libraries of phosphorus ligands is at the core of catalyst screening for the optimization of industrially relevant process. Among these processes, hydrogenation, hydroformylation and cross coupling reactions strongly depends on such methodology. In this regard, the availability of structurally and electronically diverse phosphorus ligands is essential to fully explore the relationship between the structure and the activity of the catalyst, and therefore, is crucial in choosing the best catalyst for a given reaction. Over the last decades, great advances have been achieved in the prediction of catalyst activity however catalyst screening will remain necessary and ligands must be assessed experimentally.
In this context, the accessibility to new phosphorus ligands is of utmost importance to expand the ligand space of existing catalysts. However, challenging synthetic steps with high reactive and pyrophoric compounds and intermediated can impair the synthesis of such new ligands. Therefore the need for new synthetic methods to prepare new ligand structures is highly welcome. In this light, the new synthetic method for the synthesis of di tert-alkyl substituted phosphines (an essential building block in the synthesis of phosphorus ligand), was recently published in ACS Catalysis by Ball and coworkers (DOI: 10.1021/acscatal.0c01414). The authors reported that the alkylation of PH3 by various alkyl-substituted esters can be achieved, producing diverse air stable and odorless di tert-alkyl phosphines (DTAP). Through this unusual SN1 type reaction, various DTAP building blocks were produced and subsequently used in the synthesis of new phosphorus ligands of the JohnPhos family, demonstrating the ability of the current method to access an unexplored ligand space. Additionally, the used PH3 could be generated by hydrolysis of Zn3P2, making this method safer than other existing methods generally employed in the synthesis of phosphines.
The first discovery made by the authors is a new way to generate PH3 by protonolysis of (cheap and air-stable) Zn3P2 using aqueous HCl solution. The PH3 is generated ex situ in a two-chamber reactor, which is then available for subsequent reaction taking place in the second chamber of the reactor. Kinetic measurements show that the reaction of hydrolysis occurs slow enough to be performed in a safe manner. This method avoids the handling of a pressurized cylinder of PH3 and prevents the use of hazardous reagents generally used in the synthesis of phosphine ligands (such as PCl3 and Grignard reagents).
Thereafter, the authors identified an unprecedented path to access new di tert-alkyl phosphines. Instead of using the classic approach generally used for the synthesis of phosphines (PCl3, Grignard reagents), the authors describe in this work a SN1 type reaction between the -generated PH3 and an ester to form the di-tert-alkylphosphino (DTAP) building blocks in high yields. The alkylation of PH3 could be successfully performed in neat conditions and at room temperature affording the DTAP as a bench-stable and odorless solid and are thus easy to handle and store. Among the previously attempted methods for the alkylation of PH3 (SN2 reactions or hydrophosphination), none of them allow for the installation of tert-alkyl substituents of the phosphorus. Under optimized conditions, the method was extended to various tert-alkyl esters (including cyclic esters and esters of aryl bromide), affording a range of corresponding DTAP building blocks including the first example of a C-stereogenic di-tertalkyl phosphine.
Investigation of the reaction mechanism indicates that the formed carbocation must be accessible and should not be subject to intramolecular elimination (versus intermolecular reaction with PH3). In particular, several deuterium-labelled experiments (using PD3 or CD3-labelled tert-alkyl esters) were performed, revealing that a reversible elimination of the carbocation takes place prior to the reaction between the ester and PH3. However, the investigation also reveals that primary, secondary and sterically hindered alkyl ester are unreactive, limiting the method to the production of only di tert-alkyl phosphines.
After reaction with a base, the new phosphonium salts can be used as a very useful platform for the synthesis of important intermediates and ligands such as phosphine-borane complexes, P-chlorinated phosphines, secondary phosphine oxides and analogues of the cataCXium ligands. In this paper, the methodology was applied for the synthesis of new phosphorus ligands of the JohnPhos family which previously could not be synthesized with other methods. Using NMR and X-ray spectroscopy, the study shows that the newly synthesized DTAP-phosphines have well-defined physical and spectroscopic properties, therefore allowing for the extension of the ligand space of the JohnPhos family.
Finally, the new analogues of the JohnPhos family were used in the Suzuki-Miyaura coupling, in order to highlight the benefit on catalysis of the extended ligand space using this method. This was assessed by measuring the chemoselectivity obtained upon competition experiments using regioisomeric aryl bromides. Although the range of the chemoselectivity obtained shows the effectiveness of the extended ligand space, no correlation between the various ligand parameters and the chemoselectivity was observed. This lack of correlation points out the necessity of the experimental testing of new ligands when searching for improved catalytic properties.
This work highlights the importance of new ligand synthesis methodology to make catalysts that reaches the desired selectivity and activity during process optimization. We hope that this work can encourage other research in the look for new methods to generates novel ligand structures.
About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical and Bulk chemical industry to solve their most challenging projects.
Article: “Expanding Ligand Space: Preparation, Characterization, and Synthetic Applications of Air-Stable, Odorless Di-tertalkylphosphine Surrogates”
By: Thomas Barber, Stephen P. Argent, and Liam T. Ball
ACS Catal. 2020, 10, 5454−5461