Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling.

Yiming Zhao,Benjamin R. Buckley,Huy van Nguyen,Philip Craven,John S. Fossey,Louise Male

doi:10.1021/acs.organomet.8b00539

Yiming Zhao, Benjamin R. Buckley + Show 4 more

Open Access

https://doi.org/10.1021/acs.organomet.8b00539

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Abstract

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD-obtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki–Miyaura cross-coupling products, from which 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns.

Highlights

Click chemistry, as defined by Sharpless and co-workers,[1−4] has transformed the face, and accessibility to the nonspecialist of molecular linking strategies
Copper-catalyzed triazole formation has been exploited in a wide range of scenarios[21] and has been the subject of various mechanistic studies,[22−26] leading to the proposal of a binuclear transition state involving two copper atoms. 1,2,3-Triazole derivatives have been employed as nitrogen-coordinating ligands,[27] e.g. in N,N′,28−34 N,S,29 N,Se-29 and cyclometalated[35−37] bidentate coordination complexes
Triazolenitrogens’ may not be completely innocent in the coordination environment created by these ligands, with a nitrogen coordination complex being characterized by XRD in one case

Summary

■ INTRODUCTION

As defined by Sharpless and co-workers,[1−4] has transformed the face, and accessibility to the nonspecialist of molecular linking strategies. Sterically hindered, phosphorus-containing ligands have found application outside of the palladium catalysis arena; steric parameters appear to be important in a variety of gold-mediated transformations.[108−110] Steric and electronic parameters of phosphine ligands have been a subject of study for more than 40 years.[111] More recent contributions have built upon Tolman’s concept of cone angle as a descriptor of the steric bulk a ligand imparts about a metal, resulting in a parameter known as buried volume (%VBur) coming to the fore.[112] Cavallo and co-workers have developed a free webbased tool for the calculation of %VBur, named SambVca.[113] This parametrization of ligands, using both spectroscopic measurements and calculated properties (using principle component analysis for example), has facilitated exceptional ligand design and optimization across a range of catalyzed reactions.[114−116]. Cross-coupling catalysis manifolds that provide access to increasingly three-dimensional products,[117] and those directly delivering products with leador drug-like properties[118] without need of protecting group removal or further derivatization are desired and less-well explored.[77]

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES