Deciphering complexity in Pd–catalyzed cross-couplings

George E. Clarke, James D. Firth, Lyndsay A. Ledingham, Chris S. Horbaczewskyj, Richard A. Bourne, Joshua T.W. Bray, Poppy L. Martin, Jonathan B. Eastwood, Rebecca Campbell, Alex Pagett, Duncan J. MacQuarrie, John M. Slattery, Jason M. Lynam, Adrian C. Whitwood, Jessica Milani, Sam Hart, Julie Wilson*, Ian J.S. Fairlamb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.

Original languageEnglish
Article number3968
Number of pages15
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 10 May 2024

Bibliographical note

Funding Information:
We are grateful to Chemspeed Technologies Ltd to a Partnership with the University of York which led to the embedment of an ISYNTH robotic platform within our laboratories, with particular thanks to Christian Dittrich, Jake Grace, Stephane Rickling, and Andrew Stephenson for supporting our efforts with technical training and maintenance. We have been principally funded by the EPRSC for this research (EP/S009965/1; \u201CA Fully-Automated Robotic System for Intelligent Chemical Reaction Screening\u201D) and supported by EPSRC IAA awards and a Centre for Future Health (\u201CCFH1 Partnership\u2014Pharmaceutical Optimization using a Laboratory Automated Reaction Intelligent System (POLARIS)\u201D) by the University of York. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115360, resources of which are composed of financial contributions from the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) and EFPIA companies\u2019 in-kind contributions (to L.A.L., D.J.M. and I.J.S.F.). The research was supported in part by another EPSRC grant, with follow-on funding for C.S.H. and J.B.E. (EP/W031914/1). I.J.S.F. and J.M.L. are currently supported by Royal Society Industry Fellowships. R.A.B. was supported by the Royal Academy of Engineering under the Research Chairs and Senior Research Fellowships scheme.

Funding Information:
We are grateful to Chemspeed Technologies Ltd to a Partnership with the University of York which led to the embedment of an ISYNTH robotic platform within our laboratories, with particular thanks to Christian Dittrich, Jake Grace, Stephane Rickling, and Andrew Stephenson for supporting our efforts with technical training and maintenance. We have been principally funded by the EPRSC for this research (EP/S009965/1; \u201CA Fully-Automated Robotic System for Intelligent Chemical Reaction Screening\u201D) and supported by EPSRC IAA awards and a Centre for Future Health (\u201CCFH1 Partnership\u2014Pharmaceutical Optimization using a Laboratory Automated Reaction Intelligent System (POLARIS)\u201D) by the University of York. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115360, resources of which are composed of financial contributions from the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) and EFPIA companies\u2019 in-kind contributions (to L.A.L., D.J.M. and I.J.S.F.).\u00A0The research was supported in part by another EPSRC grant, with follow-on funding for C.S.H. and J.B.E. (EP/W031914/1). I.J.S.F. and J.M.L. are currently supported by Royal Society Industry Fellowships.\u00A0R.A.B. was supported by the Royal Academy of Engineering under the Research Chairs and Senior Research Fellowships scheme.

Publisher Copyright:
© The Author(s) 2024.

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