Nickel‐catalyzed P ‐arylation of HP(= O)(R/OR) 2 nucleophiles with (hetero)aryl chlorides enabled by DalPhos ligation

Michael J. Cotnam; T. Kieran Redpath; Catherine E. Weetman; Patrick L. DeRoy; David J. Nelson; Mark Stradiotto

doi:10.1002/chem.202502189

Nickel‐catalyzed P ‐arylation of HP(= O)(R/OR) 2 nucleophiles with (hetero)aryl chlorides enabled by DalPhos ligation

Michael J. Cotnam, T. Kieran Redpath, Catherine E. Weetman, Patrick L. DeRoy, David J. Nelson^*, Mark Stradiotto^*

^*Corresponding author for this work

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Herein we disclose our development of broadly useful C-P cross-couplings of (hetero)aryl chlorides and HP(O)(R)2 or HP(O)(OR)2 nucleophiles, enabled by use of nickel/DalPhos-based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility of shorter or milder reactions was demonstrated with one specific example. The ability to apply such transformations on gram scale, and in the P-arylation of active pharmaceutical ingredients (APIs) (i.e., chloroquine and clozapine) was also shown. Also described are our findings arising from the computational modelling of such cross-coupling reactions by use of density functional theory (DFT) calculations, which confirmed the clear preference for C-P bond formation involving three-centered reductive elimination through substrate PV pathways.

Original language	English
Article number	e02189
Number of pages	9
Journal	Chemistry - A European Journal
Volume	31
Issue number	59
Early online date	15 Sept 2025
DOIs	https://doi.org/10.1002/chem.202502189
Publication status	Published - 22 Oct 2025

Funding

We are grateful to the NSERC of Canada (Discovery Grant for M.S. RGPIN-2019–04288; Alliance Award ALLRP 561675–21), Paraza Pharma Inc., and Dalhousie University for their financial support of this work. We also thank Dr. Michael Lumsden and Mr. Xiao Feng (Dalhousie) for technical assistance in the acquisition of NMR and MS data. Dr. Tom Corrie (Syngenta) is thanked for helpful discussions. TKR, DJN, and CEW thank Syngenta and the UK Research and Innovation Engineering and Physical Sciences Research Council (UKRI EPSRC) for an Industrial CASE studentship to TKR (EP/W522260/1), and the UKRI Natural Environment Research Council (NERC) for a UK-Canada Globalink Doctoral Exchange Scheme Award (NE/X00709X/1). Calculations supporting this work were performed using the ARCHIE-WeSt High Performance Computer hosted at the University of Strathclyde (www.archie-west.ac.uk) and we thank Jonathan Buzzard, Dr. Karina Kubiak-Ossowska, and Dr. Richard Martin for their assistance with this facility.

Keywords

C‐P cross‐coupling
density functional theory
nickel
DalPhos
P‐arylation

Access to Document

10.1002/chem.202502189Licence: CC BY 4.0

Cotnam-etal-CAEJ-2025-Nickel-catalyzed-P-arylation-of-HP-O-R-OR-2-nucleophilesFinal published version, 2.17 MBLicence: CC BY 4.0

1 Finished
1 Active

Industrial CASE Account - University of Strathclyde 2021 | Redpath, Thomas
Nelson, D. (Principal Investigator), Weetman, C. (Co-investigator) & Redpath, T. (Research Co-investigator)
EPSRC (Engineering and Physical Sciences Research Council)
1/09/21 → 1/03/26
Project: Research Studentship Case - Internally allocated
Investigating Nickel-Catalysed C-P Cross-Coupling (UKRI-MITACS (Redpath) Global Research Placement)
Nelson, D. (Principal Investigator)
NERC (Natural Environment Research Council)
1/09/22 → 29/02/24
Project: Research

ARCHIE-WeSt (UOSHPC)
Martin, R. (Manager)
University Of Strathclyde
Facility/equipment: Facility

Cite this

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title = "Nickel‐catalyzed P ‐arylation of HP(= O)(R/OR) 2 nucleophiles with (hetero)aryl chlorides enabled by DalPhos ligation",

abstract = "Herein we disclose our development of broadly useful C-P cross-couplings of (hetero)aryl chlorides and HP(O)(R)2 or HP(O)(OR)2 nucleophiles, enabled by use of nickel/DalPhos-based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility of shorter or milder reactions was demonstrated with one specific example. The ability to apply such transformations on gram scale, and in the P-arylation of active pharmaceutical ingredients (APIs) (i.e., chloroquine and clozapine) was also shown. Also described are our findings arising from the computational modelling of such cross-coupling reactions by use of density functional theory (DFT) calculations, which confirmed the clear preference for C-P bond formation involving three-centered reductive elimination through substrate PV pathways.",

keywords = "C‐P cross‐coupling, density functional theory, nickel, DalPhos, P‐arylation",

author = "Cotnam, {Michael J.} and Redpath, {T. Kieran} and Weetman, {Catherine E.} and DeRoy, {Patrick L.} and Nelson, {David J.} and Mark Stradiotto",

year = "2025",

month = oct,

day = "22",

doi = "10.1002/chem.202502189",

language = "English",

volume = "31",

journal = "Chemistry - A European Journal",

issn = "0947-6539",

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T1 - Nickel‐catalyzed P ‐arylation of HP(= O)(R/OR) 2 nucleophiles with (hetero)aryl chlorides enabled by DalPhos ligation

AU - Cotnam, Michael J.

AU - Redpath, T. Kieran

AU - Weetman, Catherine E.

AU - DeRoy, Patrick L.

AU - Nelson, David J.

AU - Stradiotto, Mark

PY - 2025/10/22

Y1 - 2025/10/22

N2 - Herein we disclose our development of broadly useful C-P cross-couplings of (hetero)aryl chlorides and HP(O)(R)2 or HP(O)(OR)2 nucleophiles, enabled by use of nickel/DalPhos-based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility of shorter or milder reactions was demonstrated with one specific example. The ability to apply such transformations on gram scale, and in the P-arylation of active pharmaceutical ingredients (APIs) (i.e., chloroquine and clozapine) was also shown. Also described are our findings arising from the computational modelling of such cross-coupling reactions by use of density functional theory (DFT) calculations, which confirmed the clear preference for C-P bond formation involving three-centered reductive elimination through substrate PV pathways.

AB - Herein we disclose our development of broadly useful C-P cross-couplings of (hetero)aryl chlorides and HP(O)(R)2 or HP(O)(OR)2 nucleophiles, enabled by use of nickel/DalPhos-based catalysts. These typically use 5 mol% nickel at 110 °C for 18 hours, but the feasibility of shorter or milder reactions was demonstrated with one specific example. The ability to apply such transformations on gram scale, and in the P-arylation of active pharmaceutical ingredients (APIs) (i.e., chloroquine and clozapine) was also shown. Also described are our findings arising from the computational modelling of such cross-coupling reactions by use of density functional theory (DFT) calculations, which confirmed the clear preference for C-P bond formation involving three-centered reductive elimination through substrate PV pathways.

KW - C‐P cross‐coupling

KW - density functional theory

KW - nickel

KW - DalPhos

KW - P‐arylation

U2 - 10.1002/chem.202502189

DO - 10.1002/chem.202502189

M3 - Article

SN - 0947-6539

VL - 31

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 59

M1 - e02189

ER -

Nickel‐catalyzed P ‐arylation of HP(= O)(R/OR) 2 nucleophiles with (hetero)aryl chlorides enabled by DalPhos ligation

Abstract

Funding

Keywords

Access to Document

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Projects

Industrial CASE Account - University of Strathclyde 2021 | Redpath, Thomas

Investigating Nickel-Catalysed C-P Cross-Coupling (UKRI-MITACS (Redpath) Global Research Placement)

Equipment

ARCHIE-WeSt (UOSHPC)

Cite this