A phosphine free, inorganic base free, one-pot tandem Mizoroki–Heck olefination/direct arylation/hydrogenation sequence, to give multicyclic alkylated heteroarenes
A phosphine free, inorganic base free, one-pot tandem Mizoroki–Heck olefination/direct arylation/hydrogenation sequence, to give multicyclic alkylated heteroarenes
One-pot processes which facilitate a number of tandem reactions, represent an environmentally friendly approach to building molecular complexity. In addition, there are significant cost and time saving benefits. However, unearthing multiple reactions that display substrate, reagent and solvent compatibility across two or more reactions, is not straightforward. This is even more pronounced when using catalysts, which by their nature, are present in small amounts and thus susceptible to poisoning. Herein we describe a phosphine-free, inorganic base free, multi-step, one-pot reaction sequence which enables the rapid synthesis of complex, medicinally relevant heterocycles in excellent yields. This Pd-catalysed approach combines Heck olefination, C–H activation, and hydrogenation, and the same pre-catalyst is involved in the three mechanistically distinct processes. Quinolines as substrates are used in the main, but we also provide a neat extension to pyridines and simple aryl substrates. Deuterium (D2) incorporation can be facilitated through use of the COware apparatus in the reduction step. Favourable mass productivity (MP), environmental impact factor (EF), solvent intensity (SI) and process mass intensity (PMI) values are reported. While the motivation to avoid problematic additives (inorganic base and P-ligands) and problematic solvent (DMA and NMP) was driven by a green agenda, the removal of reagents and additives in the context of one-pot strategies might also serve to reduce the bad actors and improve yields in one-pot processes.
5654-5660
Kehoe, Roberta A.
fe06d727-db10-420d-a03a-a4e26042010e
Light, Mark
cf57314e-6856-491b-a8d2-2dffc452e161
Jones, David J.
7985500f-79fb-43c0-8d19-b563062c0aeb
McGlacken, Gerard P.
7232768a-94ff-4794-81b3-1467726505e0
17 July 2023
Kehoe, Roberta A.
fe06d727-db10-420d-a03a-a4e26042010e
Light, Mark
cf57314e-6856-491b-a8d2-2dffc452e161
Jones, David J.
7985500f-79fb-43c0-8d19-b563062c0aeb
McGlacken, Gerard P.
7232768a-94ff-4794-81b3-1467726505e0
Kehoe, Roberta A., Light, Mark, Jones, David J. and McGlacken, Gerard P.
(2023)
A phosphine free, inorganic base free, one-pot tandem Mizoroki–Heck olefination/direct arylation/hydrogenation sequence, to give multicyclic alkylated heteroarenes.
Green Chemistry, 25 (14), .
(doi:10.1039/D3GC01403G).
Abstract
One-pot processes which facilitate a number of tandem reactions, represent an environmentally friendly approach to building molecular complexity. In addition, there are significant cost and time saving benefits. However, unearthing multiple reactions that display substrate, reagent and solvent compatibility across two or more reactions, is not straightforward. This is even more pronounced when using catalysts, which by their nature, are present in small amounts and thus susceptible to poisoning. Herein we describe a phosphine-free, inorganic base free, multi-step, one-pot reaction sequence which enables the rapid synthesis of complex, medicinally relevant heterocycles in excellent yields. This Pd-catalysed approach combines Heck olefination, C–H activation, and hydrogenation, and the same pre-catalyst is involved in the three mechanistically distinct processes. Quinolines as substrates are used in the main, but we also provide a neat extension to pyridines and simple aryl substrates. Deuterium (D2) incorporation can be facilitated through use of the COware apparatus in the reduction step. Favourable mass productivity (MP), environmental impact factor (EF), solvent intensity (SI) and process mass intensity (PMI) values are reported. While the motivation to avoid problematic additives (inorganic base and P-ligands) and problematic solvent (DMA and NMP) was driven by a green agenda, the removal of reagents and additives in the context of one-pot strategies might also serve to reduce the bad actors and improve yields in one-pot processes.
Text
d3gc01403g
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Accepted/In Press date: 20 June 2023
Published date: 17 July 2023
Additional Information:
Funding Information:
The authors would like to thank Dr Denis Lynch of University College Cork for providing NMR services, the Science Foundation Ireland (grant number SFI/12/IP/1315) and the Synthesis and Solid State Pharmaceutical Centre (SSPC) (SFI/12/RC/2275 and SFI/12/RC2275_P2). We would like to thank Thermo Fisher Scientific in Cork for helping with the scale-up reactions.
Identifiers
Local EPrints ID: 481533
URI: http://eprints.soton.ac.uk/id/eprint/481533
ISSN: 1463-9262
PURE UUID: c38bef36-c927-48c2-8cca-544fd7697dfc
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Date deposited: 31 Aug 2023 16:53
Last modified: 18 Mar 2024 02:50
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Author:
Roberta A. Kehoe
Author:
David J. Jones
Author:
Gerard P. McGlacken
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