Phosphino-Triazole Ligands for Palladium-Catalysed Cross-Coupling

17 July 2018, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesised and used as ligands for palladium-catalysed Suzuki-Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca 2.0 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 modelling 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 ten of the most lead-like were successfully synthesised. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimisation in drug discovery campaigns.

Keywords

phosphine
Suzuki-Miyaura
Palladium
Cross-coupling
Triazole
Click chemistry
crystal structure
LLAMA
lead-like
SambVca
steric map
buried volume

Supplementary materials

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ESI 20180717
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LLAMA analysis Fig09
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17a
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17a
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18a
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18a
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29g
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29g
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42
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42
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43
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43
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